Azabicyclic compounds for the treatment of disease

ABSTRACT

The invention provides compounds of Formula I:  
                 
 
     wherein Azabicyclo is  
                 
 
     These compounds may be in the form of pharmaceutical salts or compositions, may be in pure enantiomeric form or racemic mixtures, and are useful in pharmaceuticals in which α7 is known to be involved.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. provisionalapplication Serial No. 60/357926 filed on 19 February 2002, under 35 USC1 19(e)(i), which is incorporated herein by reference in their entirety.

FIELD OF INVENTION

[0002] Nicotinic acetylcholine receptors (nAChRs) play a large role incentral nervous system (CNS) activity. Particularly, they are known tobe involved in cognition, learning, mood, emotion, and neuroprotection.There are several types of nicotinic acetylcholine receptors, and eachone appears to have a different role in regulating CNS function.Nicotine affects all such receptors, and has a variety of activities.Unfortunately, not all of the activities are desirable. In fact, one ofthe least desirable properties of nicotine is its addictive nature andthe low ratio between efficacy and safety. The present invention relatesto molecules that have a greater effect upon the α7 nAChRs as comparedto other closely related members of this large ligand-gated receptorfamily. Thus, the invention provides compounds that are active drugmolecules with fewer side effects.

[0003] The invention also concerns the synthesis of and isolation ofintermediates and final compounds. Specifically, the present inventionconcerns the selective synthesis of(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine or salts thereof.

BACKGROUND OF THE INVENTION

[0004] Cell surface receptors are, in general, excellent and validateddrug targets. nAChRs comprise a large family of ligand-gated ionchannels that control neuronal activity and brain function. Thesereceptors have a pentameric structure. In mammals, this gene family iscomposed of nine alpha and four beta subunits that co-assemble to formmultiple subtypes of receptors that have a distinctive pharmacology.Acetylcholine is the endogenous regulator of all of the subtypes, whilenicotine non-selectively activates all nAChRs.

[0005] The α7 nAChR is one receptor system that has proved to be adifficult target for testing. Native α7 nAChR is not routinely able tobe stably expressed in most mammalian cell lines (Cooper and Millar, J.Neurochem., 1997, 68(5):2140-51). Another feature that makes functionalassays of α7 nAChR challenging is that the receptor is rapidly (100milliseconds) inactivated. This rapid inactivation greatly limits thefunctional assays that can be used to measure channel activity.

[0006] Recently, Eisele et al. has indicated that a chimeric receptorformed between the N-terminal ligand binding domain of the α7 nAChR(Eisele et al., Nature, 366(6454), p 479-83, 1993), and the pore formingC-terminal domain of the 5-HT₃ receptor expressed well in Xenopusoocytes while retaining nicotinic agonist sensitivity. Eisele et al.used the N-terminus of the avian (chick) form of the α7 nAChR receptorand the C-terminus of the mouse form of the 5-HT₃ gene. However, underphysiological conditions the α7 nAChR is a calcium channel while the5-HT₃R is a sodium and potassium channel. Indeed, Eisele et al. teachesthat the chicken α7 nAChR/mouse 5-HT₃R behaves quite differently thanthe native α7 nAChR with the pore element not conducting calcium butactually being blocked by calcium ions. WO 00/73431 A2 reports on assayconditions under which the 5-HT₃R can be made to conduct calcium. Thisassay may be used to screen for agonist activity at this receptor.

[0007] U.S. Pat. No. 5,977,144 discloses compositions for benzylidene-and cinnamylidene-anabaseines and methods for using these compositionsfor treating conditions associated with defects or malfunctioning ofnicotinic subtypes brain receptors. These compositions target the α7receptor subtype with little or no activation of the α4β2 or otherreceptor subtypes.

[0008] U.S. Pat. No. 5,599,937 discloses heteroaromatic quinuclidinesused for treating diseases related to muscarinic receptor function.

[0009] U.S. Pat. No. 5,561,149 discloses the use of a mono or bicycliccarbocyclic, or heterocyclic carboxylic acid, ester or amide or animidazolyl carbazol in the manufacture of a medicament suitable for thetreatment of stress-related psychiatric disorders, for increasingvigilance, for the treatment of rhinitis or serotonin-induced disordersand/or coadministration with another active agent to increase thebioavailability thereof, or for nasal administration.

[0010] U.S. Pat. No. 5,543,426 discloses the use of certain3,7-disubstituted indole compounds for treating depression or cognitivedisorders.

[0011] U.S. Pat. No. 5,434,161 discloses imidazopyridines asserotonergic 5-HT₃ antagonists.

[0012] U.S. Pat. No. 5,362,740 discloses dihydrobenzofuran carboxamidesuseful in treating CNS disorders, but motility disorders, and/or emisisand/or pain in mammals, and/or migraine.

[0013] U.S. Pat. No. 5,352,685 discloses thieno[3,2-b]pyridinederivatives effective for the prevention and therapeutical treatment ofthe symptoms caused by gastric hypanakinesis, such as heartburn,abdominal distension feeling, anorexia, unpleasant feeling on upperabdomen, abdominalgia, nausea, vomiting, etc. caused by the underlyingdiseases such as acute and chronic gastritis, stomach and duodenumulcer, gastroneurosis, gastroptosis, etc.

[0014] U.S. Pat. No. 5,342,845 discloses indole derivatives and drugs.The compound of the invention is disclosed as being effective as agastrointestinal motor activity regulator, antimigraine, antipsychoticor antianxiety drug and for dementia or orthostatic hypotension.

[0015] U.S. Pat. No. 5,322,951 discloses certain1-(2,3-dihydro-indole)carbonyl intermediates useful for preparing1-(2,3-dihydro)-1-carboxamide final products that possess 5-HTM-receptor antagonist activity.

[0016] U.S. Pat. No. 5,272,154 discloses 3,7 substituted indole andindazole compounds and pharmaceutical compositions containing them andare disclosed as being useful for the treatment of psychiatricdisorders.

[0017] U.S. Pat. No. 5,217,975 discloses azabicyclic compounds fortreating dementia.

[0018] U.S. Pat. No. 5,114,947 discloses a method for alleviatinganxiety using benzobicyclic carboxamides.

[0019] U.S. Pat. No. 5,039,680 discloses 5-HT₃ antagonists in preventingor reducing dependency on dependency-inducing agents.

[0020] U.S. Pat. No. 5,001,133 discloses substituted benzoic acidheterocyclic amides and esters as being serotonin M antagonists.

[0021] U.S. Pat. No. 4,985,437 discloses the use of certain compoundswhich act as antagonists of 5-hydroxytryptamine (5-HT) at 5-HT₃receptors for the treatment of cognitive disorders such as attentionaland memory deficits and dementia states.

[0022] U.S. Pat. No. 4,983,600 discloses heterocyclic compounds usefulas 5-HT₃ antagonists.

[0023] U.S. Pat. No. 4,973,594 discloses the use of compounds which actas antagonists of 5-hydroxytryptamine (5-HT) at 5-HT₃ receptors for thetreatment of depression.

[0024] U.S. Pat. No. 4,937,247 discloses 1-acyl indazoles that aredisclosed as having 5-HT₃ antagonist activity.

[0025] U.S. Pat. No. 4,935,511 discloses benzoxazine and benzoxazepincarboxamide 5-HT₃ antagonists properties including CNS, anti-emetic andgastric prokinetic activity and which are void of any significant D₂receptor binding affinity.

[0026] U.S. Pat. No. 4,921,982 discloses5-halo-2,3-dihydro-2,2-dimethylbenzofuran-7-carboxylic acids which areuseful as intermediates for 5-HT₃ antagonists.

[0027] U.S. Pat. No. 4,920,219 discloses substituted saturated andunsaturated indole quinoline and benzazepine carboxamides and theirvaluable use as 5-HT₃ antagonists having CNS and gastric prokineticactivity void of any significant D₂ receptor binding properties.

[0028] U.S. Pat. No. 4,920,127 discloses substituted indoles and theiruse as 5-HT₃ receptor antagonists.

[0029] U.S. Pat. No. 4,910,193 discloses treatment of gastrointestinaldisorders.

[0030] U.S. Pat. No. 4,888,353 discloses carboxamides useful asantiemetic or antipsychotic agents.

[0031] U.S. Pat. No. 4,882,327 discloses certain heterocyclicN-substituted carboxamides having 5-HT₃ receptor antagonist activity.

[0032] U.S. Pat. No. 4,845,092 discloses a method of treatment ofvisceral pain in mammals, including humans.

[0033] U.S. Pat. No. 4,835,162 discloses agonists and antagonists tonicotine as smoking deterrents.

[0034] U.S. Pat. No. 4,822,795 discloses pharmaceutically useful estersand amides.

[0035] U.S. Pat. No. 4,803,199 discloses pharmaceutically usefulheterocyclic acid esters and amides or alkylene bridged peperidines asserotonin M antagonists.

[0036] U.S. Pat. No. 4,798,829 discloses 1-azabicyclo[3.2.2]nonanederivatives having gastric motility enhancing activity and/oranti-emetic activity and/or 5-HT receptor antagonist activity.

[0037] U.S. Pat. No. 4,797,406 discloses amides and esters containingbridged piperidines and use as serotonin M antagonists.

[0038] U.S. Pat. No. 4,721,720 discloses a method of treating emesis,anxiety and/or irritable bowl syndrome.

[0039] U.S. Pat. No. 4,612,319 discloses bridged quinolizinidinylamides,compositions containing them and methods for their use.

[0040] U.S. Pat. No. 4,605,652 discloses a method of enhancing memory orcorrecting memory deficiency with arylamido (andarylthioamido)-azabicycloalkanes, and the pharmaceutically acceptableacid addition salts, hydrates and alcoholates thereof.

[0041] WO 01/76576 A2 discloses a pharmaceutical composition fortreatment of acute, chronic pain and/or neuropathic pain and migraines.

[0042] WO 01/60821 A1 discloses novel biarylcarboxamides and their usein therapy, especially in the treatement of prophylaxis of psychotic andintellectual impairment conditions.

[0043] WO 01/36417 A1 discloses novel N-azabicyclo-amide derivatives anduse in therapy, especially in the treatment of prophylaxis of psychoticdisorders and intellectual impairment disorders.

[0044] WO 00/73431 A2 discloses two binding assays to directly measurethe affinity and selectivity of compounds at the α7 nAChR and the5-HT₃R. The combined use of these functional and binding assays may beused to identify compounds that are selective agonists of the α7 nAChR.

[0045] WO 99/20633 discloses benzoazine derivatives having an antagonistactivity for 5-HT₃/5-HT₄ receptors.

[0046] WO 97/35860 discloses novel benzimidazol derivatives having anaffinity for the serotoninergic 5-HT₃/5-HT₄ receptors.

[0047] WO 96/33186 discloses substituted dihydrobenzofuran derivativesas 5-HT₄ agonists.

[0048] WO 95/27490 discloses serotonin antagonists (5-HT₃) for treatingfibromyalgia.

[0049] WO 95/04742 discloses tropyl 7-azaindol-3-ylcarboxyamides asantitussive agents.

[0050] WO 92/10494 discloses novel compounds that are 5-HT₃ receptorantagonists.

[0051] WO 91/17161 discloses isoquinoline amides and esters as 5-HT₃receptor antagonists.

[0052] WO 91/09593 discloses 5-HT₃ antagonists for treatment of nausea,bradycardia or hypotension associated myocardial instability.

[0053] WO 90/14347 A as abstracted in chemical abstract 1991:143,158discloses N-quinuclidinyl-indolecarboxamide derivatives as beingantiemetics.

[0054] EP 512 350 A2 discloses 3-(indolyl-2-carboxamido) quinuclidinesuseful for treating diseases characterized by an excess or enhancedsensitivity to serotonin, e.g., psychosis, nausea, vomiting, dementia orother cognitive diseases, migraine, diabetes. The compound may be usedto control anxiety, aggression, depression, and pain. The compounds aredisclosed as serotonin 5-HT₃ antagonists.

[0055] EP 496 064 A1 discloses a process for the preparation ofsubstituted benzofuran derivatives. The compounds are disclosed as beinguseful 5-HT₃ receptor antagonists.

[0056] EP 483 836 A1 discloses pyrazolo[1,5-a]pyridine-3-carboxylic acidderivatives, their preparation process, and serotonin receptorantagonists containing them as active ingredients.

[0057] DE 3810552 A1 discloses esters and amides of indolyl-,benzo[b]thiophenyl-, benzo[b]furancarboxylic acids or 4-amino-2methoxy-benzoic acids with N-heterocyclic or N-heterobicyclic alcoholsor amines. The compounds disclosed have activity against pain especiallymigraine, as an anti-arrhythmic for gastrointestinal disturbances,stomach disturbances, gastritis ulcer, gall bladder, spastic colon,Crohn's disease, ulcerative colitis, carcinoid syndrome, diarrhea ofvarious types. The compounds are also disclosed as speeding stomachemptying, controlling gastro duodenal and gastro esophageal reflux,disturbances of esophageal motility, hiatal hernia, cardiacinsufficiency, hypotonic stomach, paralytic ileus, manic depressivepsychosis and other psychoses. The compounds are also disclosed asuseful for stress related diseases, senility, and enhancement of nasalabsorption of other agents, e.g., in the treatment of emesis.

[0058] In Bioorg. & Med.Chem. Lett. 11 (2001) 319-321, the 5-HT₃antagonist tropisetron (ICS 205-930) is discussed as a potent andselective x7 nicotinic receptor partial agonist.

[0059] In Behavioral Brain Res., 113 (2000) 169-181, it is discussedthat the brain α7 nicotinic receptor may be an important therapeutictarget for the treatment of Alzheimer's disease using DMXBA which isknown as GTS-21.

[0060] In Bioorg. & Med. Chem. Lett. 9 (1999) 1895-1900, it is discussedthe discovery of a highly potent, functionally-selective muscarinic M₁agonist.

[0061] In Bioorg. & Med. Chem. Lett. 4 (1994) 695-698, it is discussedpyrazolo[1,5-a]pyridines and pyrazolo[1,5-b]pyridazines as 5-HT₃antagonists.

[0062] In Eur. J.Med. Chem., 34 (1999) 415-422,benzimidazole-2-carboxylic acid amides and esters are discussed as a newstructural class of 5-HT₃ ligands.

SUMMARY OF THE INVENTION

[0063] The present invention discloses compounds of the Formula I:

[0064] wherein Azabicyclo is

[0065] R₁ is H, alkyl, halogenated alkyl, cycloalkyl, substitutedphenyl, or substituted naphthyl;

[0066] R₂ is H, F, Cl, Br, I, alkyl, halogenated alkyl, substitutedalkyl, cycloalkyl, or aryl;

[0067] k is 1 or 2, provided that when k is 2, each R₂ is other than H;

[0068] R₃ is H, lower alkyl, lower substituted alkyl, or lowerhalogenated alkyl;

[0069] W₁ is O, S, or N(R₁₅);

[0070] W⁵ and W⁶ are independently H or a bond to the carbonyl ofFormula I, provided that only one of W⁵ and W⁶ is said bond and theother is H;

[0071] Each R₄ is independently H, F, Cl, Br, I, alkyl, halogenatedalkyl, substituted alkyl, alkenyl, halogenated alkenyl, substitutedalkenyl, alkynyl, halogenated alkynyl, substituted alkynyl, cycloalkyl,halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl,halogenated heterocyloalkyl, substituted heterocycloalkyl, lactamheterocylcoalkyl, phenyl, substituted phenyl, —OR₁₀, —SR₁₀, —SOR₁₀,—SO₂R₁₀, —NR₁₀C(O)R₅, —NR₁₀C(O)R₆, —NR₁₀C(O)R₈, —NR₁₀C(O)R₁₀, —N(R₁₀)₂,—NO₂, —C(O)R₁₀, —CN, —C(O)₂R₁₀, —C(O)NHR₁₀, —SCN, —S(O)NHR₁₀,—S(O)₂NHR₁₀, —NR₁₀S(O)₂R₁₀, R₅, or R₆, provided that when R₄ is—SO₁₋₂R₁₀ or —CO₁₋₂R₁₀ and R₁₀ is heterocycle, halogenated heterocycleor heterocycle substituted with 1 substitutent selected from R₁₃, acarbon in the heterocycle is bonded to the carbon or sulfur;

[0072] m is 1 or 2, provided that when m is 2 each R₄ is other than H;

[0073] R₅ is a 5-membered heteroaromatic mono-cyclic moiety containingwithin the ring 1-3 heteroatoms independently selected from the groupconsisting of —O—, ═N—, —N(R₁₆)—, and —S—, and having 0-1 substituentselected from R₉, and further having 0-3 substituents independentlyselected from F, Cl, Br, or I,

[0074] or R₅ is a 9-membered fused-ring moiety having a 6-membered ringfused to a 5-membered ring and having the formula

[0075] wherein each A is independently CR₁₄ or N, provided that only upto one A is N, E¹ and E² are independently selected from CR₁₄, O, S, orNR₁₆, and G is CR₁₄, provided that R₁₄ or R₁₆ can be a bond when—forms adouble bond and further provided that only one R₁₄ or R₁₆ can be a bondfor bonding R₅ to a moiety to which it is attached;

[0076] R₆ is a 6-membered heteroaromatic mono-cyclic moiety containingwithin the ring 1-3 heteroatoms selected from ═N— and having 0-1substituent selected from R₉ and 0-3 substituent(s) independentlyselected from F, Cl, Br, or I,

[0077] or R₆ is a 10-membered heteroaromatic bi-cyclic moiety containingwithin one or both rings 1-3 heteroatoms selected from ═N—, including,but not limited to, quinolinyl or isoquinolinyl, each 10-memberedfused-ring moiety having 0-1 substituent selected from R₉, and 0-3substituent(s) independently selected from F, Cl, Br, or I;

[0078] R₇ is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,halogenated cycloalkyl, substituted cycloalkyl, phenyl, or phenyl having0-4 substituents independently selected from F, Cl, Br, I, and R₉;

[0079] Each R₈ is independently H, alkyl, halogenated alkyl, substitutedalkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, phenyl, or phenyl substituted with 0-4 independentlyselected from F, Cl, Br, I, or R₉;

[0080] R₉ is alkyl, substituted alkyl, halogenated alky, —OR₁₁, —CN,—NO₂, —NR₁₀R₁₀;

[0081] Each R₁₀ is independently H, alkyl, cycloalkyl, heterocycloalkyl,alkyl substituted with 1 substituent selected from R₁₃, cycloalkylsubstituted with 1 substituent selected from R₁₃, heterocycloalkylsubstituted with 1 substituent selected from R₁₃, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl, orsubstituted phenyl;

[0082] Each R₁₁ is independently H, alkyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated cycloalkyl, or halogenatedheterocycloalkyl;

[0083] R₁₂ is —OR₁₁, —SR₁₁, alkyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl,substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl,—N(R₁₁)₂, —C(O)R₁₁, —NO₂, —C(O)N(R₁₁)₂, —CN, —NR₁₁C(O)R₁₁,—S(O)₂N(R₁₁)₂, or —NR₁₁S(O)₂R₁₁;

[0084] R₁₃ is —OR₁₁, —SR₁₁, —N(R₁₁)₂, —C(O)R₁₁, —SOR₁₁, —SO₂R₁₁,—C(O)NR₁₁R₁₁, —CN, —CF₃, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂, —NR₁₁S(O)₂R₁₁, or—NO₂;

[0085] Each R₁₄ is independently bond, H, alkyl, cycloalkyl,heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenatedheterocycloalkyl, substituted alkyl, substituted cycloalkyl, substitutedheterocycloalkyl, —OR₁₁, —SR₁₁, —N(R₁₁)₂, —C(O)R₁₁, —NO₂, —C(O)N(R₁₁)₂,—CN, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂, —NR₁₁S(O)₂R₁₁, F, Cl, Br, I, or abond, provided that the fused-ring moiety has 0-1 substituent selectedfrom alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenatedcycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substitutedcycloalkyl, substituted heterocycloalkyl, —OR₁₁, —SR₁₁, —N(R₁₁)₂,—C(O)R₁₁, —NO₂, —C(O)N(R₁₁)₂, —CN, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂, or—NR₁₁S(O)₂R₁₁, and further provided that the fused-ring moiety has 0-3substituent(s) selected from F, Cl, Br, or I;

[0086] R₁₅ is H, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, or substitutedheterocycloalkyl;

[0087] Each R₁₆ is independently bond, H, alkyl, halogenated alkyl,substituted alkyl, cycloalkyl, halogenated cycloalkyl, substitutedcycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, orsubstituted heterocycloalkyl;

[0088] or pharmaceutical composition, pharmaceutically acceptable salt,racemic mixture, or pure enantiomer thereof.

[0089] Embodiments of the invention may include one or more orcombination of the following.

[0090] The present invention also includes a method to treat using acompound according to Formula I or pharmaceutically acceptable saltthereof, or use of a compound according to Formula I or pharmaceuticallyacceptable salt thereof to prepare a medicament for treating, a diseaseor condition, wherein the mammal would receive symptomatic relief fromthe administration of a therapeutically effective amount of α7 nicotinicacetylcholine receptor agonist.

[0091] The compounds of Formula I are used to treat, or make amedicament to treat, a disease or condition, wherein the disease orcondition is any one or more or combination of the following: cognitiveand attention deficit symptoms of Alzheimer's, neurodegenerationassociated with diseases such as Alzheimer's disease, pre-seniledementia (mild cognitive impairment), senile dementia, schizophrenia,psychosis, attention deficit disorder, attention deficit hyperactivitydisorder, depression, anxiety, general anxiety disorder, post traumaticstress disorder, mood and affective disorders, amyotrophic lateralsclerosis, borderline personality disorder, traumatic brain injury,behavioral and cognitive problems in general and associated with braintumors, AIDS dementia complex, dementia associated with Down's syndrome,dementia associated with Lewy Bodies, Huntington's disease, Parkinson'sdisease, tardive dyskinesia, Pick's disease, dysregulation of foodintake including bulemia and anorexia nervosa, withdrawal symptomsassociated with smoking cessation and dependant drug cessation, Gillesde la Tourette's Syndrome, age-related macular degeneration, glaucoma,neurodegeneration associated with glaucoma, or symptoms associated withpain.

[0092] The compounds of Formula I are used to make pharmaceuticalcomposition(s) comprising a compound of Formula I, a pharmaceuticallyacceptable excipient, and optionally anti-psychotic agent(s), e.g., atleast one anti-psychotic agent. The pharmaceutical composition(s) isadministered so the compound of Forumla I and the agent if it is presentare to be independently administered rectally, topically, orally,sublingually, or parenterally for a therapeutically effective interval.The compound of Formula I is administered in an amount of from about0.001 to about 100 mg/kg of body weight of said mammal per day,including from about 0.1 to about 50 mg/kg of body weight of said mammalper day. One of ordinary skill in the art will know how to administerthe anti-psychotic agent(s).

[0093] In another aspect, the invention includes methods of treating amammal suffering from schizophrenia or psychosis by administeringcompounds of Formula I in conjunction with antipsychotic drug(s), e.g.,at least one anti-psychotic agent. The compounds of Formula I and theantipsychotic drugs can be administered simultaneously or at separateintervals. When administered simultaneously the compounds of Formula Iand the antipsychotic drugs can be incorporated into a singlepharmaceutical composition. Alternatively, two separate compositions,i.e., one containing compounds of Formula I and the other containingantipsychotic drugs, can be administered simultaneously.

[0094] The compounds of Formula I (Azabicyclo is I) have asymmetriccenter(s) on the quinuclidine ring. The compounds of the presentinvention include quinuclidines with the 3R configuration, 3R,2Sconfiguration, 3S configuration, or 3S configuration without a specificconfiguration at C-2, and also includes racemic mixtures, the separatestereoisomers, and compositions of varying degrees of stereochemicalpurity. For example, and not by limitation, compounds of Formula Iinclude compounds with stereospecificity including:

[0095] The compounds of Formula I (Azabicyclo is II) have asymmetriccenter(s) on the [2.2.1] azabicyclic ring at C3 and C4. The scope ofthis invention includes racemic mixtures of varying degrees ofstereochemical purities, the separate stereoisomers, and compositions ofvarying degrees of stereochemical purities of Formula I being endo-4S,endo-4R, exo-4S, exo-4R:

[0096] The endo isomer is the isomer where the non-hydrogen substituentat C3 of the [2.2.1] azabicyclic compound is projected toward the largerof the two remaining bridges. The exo isomer is the isomer where thenon-hydrogen substituent at C3 of the [2.2.1] azabicyclic compound isprojected toward the smaller of the two remaining bridges. Thus, therecan be four separate isomers: exo-4(R), exo-4(S), endo-4(R), andendo-4(S).

[0097] The compounds of Formula I (Azabicyclo is III) have asymmetriccenter(s) on the [3.2.1] azabicyclic ring at C3 and C5. The scope ofthis invention includes racemic mixtures of varying degrees ofstereochemical purities, the separate stereoisomers, and compositions ofvarying degrees of stereochemical purities of Formula I being endo-3S,5R, endo-3R, 5S, exo-3R, 5R, exo-3S, 5S:

[0098] The compounds of Formula I (Azabicyclo is IV) have asymmetriccenters on the [3.2.2] azabicyclic ring with one center being at C3 whenR₂ is absent. The scope of this invention includes racemic mixtures ofvarying degrees of stereochemical purities, the separate stereoisomers,and compositions of varying degrees of stereochemical purities ofFormula I being 3(S) and 3(R):

[0099] The compounds of Formula I (Azabicyclo V) have asymmetriccenter(s) on the [2.2.1] azabicyclic ring at C1, C4 and C5. The scope ofthis invention includes racemic mixtures of varying degrees ofstereochemical purities, the separate stereoisomers, and compositions ofvarying degrees of stereochemical purities of Formula I being(1R,4R,5S), (1R,4R,5R), (1S,4S,5R), (1S,4S,5S):

[0100] The endo isomer is the isomer where the non-hydrogen substituentat C5 of the [2.2.1] azabicyclic compound is projected toward the largerof the two remaining bridges. The exo isomer is the isomer where thenon-hydrogen substituent at C5 of the [2.2.1] azabicyclic compound isprojected toward the smaller of the two remaining bridges. Thus, therecan be four separate isomers: exo-(1R,4R,5S), exo-(1S,4S,5R),endo-(1S,4S,5S), endo-(1R,4R,5R).

[0101] The compounds of Formula I (Azabicyclo VI) have asymmetriccenter(s) on the [2.2.1] azabicyclic ring at C1, C4 and C6. The scope ofthis invention includes racemic mixtures of varying degrees ofstereochemical purities, the separate stereoisomers, and compositions ofvarying degrees of stereochemical purities of Formula I beingexo-(1S,4R,6S), exo-(1R,4S,6R), endo-(1S,4R,6R), and endo-(1R,4S,6S):

[0102] The endo isomer is the isomer where the non-hydrogen substituentat C6 of the [2.2.1] azabicyclic compound is projected toward the largerof the two remaining bridges. The exo isomer is the isomer where thenon-hydrogen substituent at C6 of the [2.2.1] azabicyclic compound isprojected toward the smaller of the two remaining bridges. Thus, therecan be four separate isomers: exo-(1S,4R,6S), exo-(1R,4S,6R),endo-(1S,4R,6R), and endo-(1R,4S,6S).

[0103] The compounds of the present invention having the specifiedstereochemistry have different levels of activity and that for a givenset of values for the variable substitutuents one isomer may bepreferred over the other isomers. Although it is desirable that thestereochemical purity be as high as possible, absolute purity is notrequired. This invention involves racemic mixtures and compositions ofvarying degrees of stereochemical purities when the Azabicyclo issubstituted with only the amide or is substituted with substituents inaddition to the amide, e.g., R₂ is alkyl. When racemic mixtures andcompositions are referenced, it is meant racemic mixtures andcompositions of varying degrees of stereochemical purities. It ispreferred to carry out stereoselective syntheses and/or to subject thereaction product to appropriate purification steps so as to producesubstantially enantiomerically pure materials. Suitable stereoselectivesynthetic procedures for producing enantiomerically pure materials arewell known in the art, as are procedures for purifying racemic mixturesinto enantiomerically pure fractions.

[0104] Stereoselective syntheses and/or subjecting the reaction productto appropriate purification steps produces substantiallyenantiomerically pure materials. Suitable stereoselective syntheticprocedures for producing enantiomerically pure materials are well knownin the art, as are procedures for purifying racemic mixtures intoenantiomerically pure fractions.

[0105] The compound of Formula I, where Azabicyclo is any one or more ofthe following: I, II, III, IV, V, or VI.

[0106] Another embodiment of the compounds of Formula I includes any oneor more or combination of the following configurations for Azabicyclo:

[0107] where (i) the compound is a mixture of diastereomers,

[0108] (ii) the compound has the R absolute stereochemistry at C-3,

[0109] (iii) the compound has the R absolute stereochemistry at C-3 andthe S absolute stereochemistry at C-2 as discussed herein and R₂ isother than H,

[0110] (iv) the compound has the S absolute stereochemistry at C-3, or

[0111] (v) the compound has the S absolute stereochemistry at C-3 and isa mixture of diastereomers at C-2 as discussed herein and R₂ is otherthan H.

[0112] Another embodiment of compounds of Formula I includes any one ormore or combination of the following configurations for Azabicyclo:

[0113] where (i) R₂ is H;

[0114] (ii) R₂ is alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, or aryl;

[0115] (iii) R₂ is alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, or aryl; or

[0116] (iv) the 2.2.1 moiety has the exo-4(S) absolute stereochemistryas discussed herein and R₂ can have any definition discussed herein.

[0117] Another embodiment of compounds of Formula I includes any one ormore or combination of the following configurations for Azabicyclo:

[0118] where (i) R₂ is H;

[0119] (ii) R₂ is F, Cl, Br, I, alkyl, halogenated alkyl, substitutedalkyl, cycloalkyl, or aryl; or

[0120] (iii) R₂ is alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, or aryl.

[0121] Another embodiment of compounds of Formula I includes any one ormore or combination of the following configurations for Azabicyclo:

[0122] where (i) R₂ is H;

[0123] (ii) R₂ is F, Cl, Br, I, alkyl, halogenated alkyl, substitutedalkyl, cycloalkyl, or aryl; or

[0124] (iii) R₂ is alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, or aryl.

[0125] Another embodiment of compounds of Formula I includes any one ormore or combination of the following configurations for Azabicyclo:

[0126] where (i) R₂ is H and k is 1;

[0127] (ii) R₂ is H and where the Azabicyclo has the absolutestereochemistry of 3R, 5R;

[0128] (iii) k is 2, where R_(2-a) is alkyl, halogenated alkyl,substituted alkyl, cycloalkyl, or aryl, and where R_(2-b) is F, Cl, Br,I, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, or aryl;

[0129] (iv) k is 1, where R₂ is alkyl, halogenated alkyl, substitutedalkyl, cycloalkyl, or aryl; or

[0130] (v) k is 1, where R₂ is F, Cl, Br, I, alkyl, halogenated alkyl,substituted alkyl, cycloalkyl, or aryl.

[0131] Another embodiment of compounds of Formula I includes any one ormore or combination of the following configurations for Azabicyclo:

[0132] where (i) R₂ is H and k is 1;

[0133] (ii) k is 2, where each R_(2-a) is alkyl, halogenated alkyl,substituted alkyl, cycloalkyl, or aryl and where each R_(2-b) is F, Cl,Br, I, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, or aryl;

[0134] (iii) k is 1, where R₂ is alkyl, halogenated alkyl, substitutedalkyl, cycloalkyl, or aryl; or

[0135] (iv) k is 1, where R₂ is F, Cl, Br, I, alkyl, halogenated alkyl,substituted alkyl, cycloalkyl, or aryl.

[0136] Another embodiment of compounds of Formula I includes any one ormore or combination of the following configurations for W:

[0137] Another group of compounds of Formula I includes compounds whereW¹ is O. Another group of compounds of Formula I includes compoundswhere W¹ is S. Another group of compounds of Formula I includescompounds where W⁵ and W⁶ are independently H or a bond. Another groupof compounds of Formula I includes compounds where W¹ is N(R₁₅). Anothergroup of compounds of Formula I includes compounds where R₁₅ isindependently any one of the following: H, alkyl, halogenated alkyl,substituted alkyl, cycloalkyl, halogenated cycloalkyl, substitutedcycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, orsubstituted heterocycloalkyl, including, but not limited to, loweralkyl, lower halogenated alkyl, or lower substituted alkyl.Surprisingly, compounds where W is attached at the five or six positionhave superior activity in the assays discussed herein compared to theother regioisomers. Another group of compounds of Formula I includescompounds where W is any one or more of the following: 5-benzofuranyl,6-benzofuranyl, 5-1H-indolyl, 6-1H-indolyl, 5-benzothienyl, or6-benzothienyl, any of which is optionally substituted at the carbon twoor three position with any one of the following: lower alkyl, includingbut not limited to, methyl, ethyl, or isopropyl; lower halogenated alkylincluding, but not limited to, trifluoromethyl, 1,1,1-trifluoroethyl, or1,1,1-trifluoro-2,2-difluoroethyl; lower alkynyl including, but notlimited to, ethynyl, or propyn-1-yl; halogen; cyano; aminocarbonyl;formyl; or acetyl. Surprisingly, we have found that the compounds havingW be benzofuranyl have better residence time in the brain and offerother benefits. Furthermore, the bond from the carbonyl of the amidemoiety should be attached to W at carbon five or six of the W moiety.Another group of compounds of Formula I includes compounds where W is5-benzofuranyl or 6-benzofuranyl, any of which is optionally substitutedat the carbon two or three position with any one of the following: loweralkyl, including but not limited to, methyl, ethyl, or isopropyl; lowerhalogenated alkyl including, but not limited to, trifluoromethyl,1,1,1-trifluoroethyl, or 1,1,1-trifluoro-2,2-difluoroethyl; loweralkynyl including, but not limited to, ethynyl, or propyn-1-yl; halogen;cyano; aminocarbonyl; formyl; or acetyl.

[0138] Another group of compounds of Formula I includes compounds whereR₁ is H. Another group of compounds of Formula I includes compoundswhere R₁ is any one of the following: alkyl, lower alkyl, halogenatedalkyl, lower halogenated alkyl, cycloalkyl, substituted phenyl, orsubstituted naphthyl, including but not limited to, methyl, benzyl andthe like.

[0139] Another group of compounds of Formula I includes compounds whereR₂ is H. Another group of compounds of Formula I includes compoundswhere R₂ includes any one of the following: F, Cl, Br, I, alkyl,halogenated alkyl, substituted alkyl, cycloalkyl, or aryl. Another groupof compounds of Formula I includes compounds where R₂ includes any oneof alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, or aryl,including, but not limited to, lower alkyl including methyl, lowerhalogenated alkyl, or lower substituted alkyl.

[0140] Another group of compounds of Formula I includes compounds whereR₃ is H. Another group of compounds of Formula I includes compoundswhere R₃ is any one of the following: lower alkyl, lower substitutedalkyl, or lower halogenated alkyl.

[0141] Another group of compounds of Formula I includes compounds whereeach R₄ is H. Another group of compounds of Formula I includes compoundswhere each R₄ independently includes any one of the following: H, F, Cl,Br, I, alkyl, lower alkyl, halogenated alkyl, lower halogenated alkyl,substituted alkyl, alkenyl, halogenated alkenyl, substituted alkenyl,alkynyl, lower alkynyl, halogenated alkynyl, substituted alkynyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocyloalkyl, substitutedheterocycloalkyl, lactam heterocylcoalkyl, phenyl, substituted phenyl,aminocarbonyl, formyl, or acetyl, —OR₁₀, —SR₁₀, —SOR₁₀, —SO₂R₁₀,—NR₁₀C(O)R₅, —NR₁₀C(O)R₆, —NR₁₀C(O)R₈, —NR₁₀C(O)R₁₀, —N(R₁₀)₂, —NO₂,—C(O)R₁₀, —CN, —C(O)₂R₁₀, —C(O)NHR₁₀, —SCN, —S(O)N(R₁₀)₂, —S(O)₂NR₁₀R₁₀,—NR₁₀S(O)₂R₁₀, R₅, or R₆. When R₄ is —SOR₁₀, —COR₁₀, —SO₂R₁₀, or —CO₂R₁₀and R₁₀ is heterocycle, halogenated heterocycle or heterocyclesubstituted with 1 substitutent selected from R₁₃, a carbon withsufficient valency in the heterocycle is bonded to the carbon or sulfur;for example, but not limitation, if R₄ were pyrrolidinylcarbonyl, itwould not be pyrrolidin-1-ylcarbonyl because the carbonyl would beattached to an atom other than carbon.

[0142] Another group of compounds of Formula I includes compounds whereeach R₈ is independently any one of the following: H, alkyl, halogenatedalkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl,substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl,substituted heterocycloalkyl, phenyl, or phenyl substituted with 0-4independently selected from F, Cl, Br, I, or R₉.

[0143] Another group of compounds of Formula I includes compounds whereeach R₁₀ is independently any one of the following: H, alkyl,cycloalkyl, heterocycloalkyl, alkyl substituted with 1 substituentselected from R₁₃, cycloalkyl substituted with 1 substituent selectedfrom R₁₃, heterocycloalkyl substituted with 1 substituent selected fromR₁₃, halogenated alkyl, halogenated cycloalkyl, halogenatedheterocycloalkyl, phenyl, or substituted phenyl.

[0144] Another group of compounds of Formula I includes compounds whereeach R₁₄ is independently any one of the following: H, alkyl,cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl,halogenated heterocycloalkyl, substituted alkyl, substituted cycloalkyl,substituted heterocycloalkyl, —OR₁₁, —SR₁₁, —N(R₁₁)₂, —C(O)R₁₁, —NO₂,—C(O)N(R₁₁)₂, —CN, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂, —NR₁₁S(O)₂R₁₁, F, Cl,Br, I, or a bond. When R₁₄ is a bond, the bond connects the moiety beingR₅ to another moiety and does not make an unsaturated bond within the R₅moiety. R₁₄ would only be a bond if no other carbon atom within R₅allows for the bond between the R₅ moiety and the other moiety to whichit is bonded.

[0145] One of ordinary skill in the art will recognize that where alkyl,halogenated alkyl, substituted alkyl, alkenyl, halogenated alkenyl,substituted alkenyl, alkynyl, halogenated alkynyl, or substitutedalkynyl is allowed, the following, respectively, are also allowed: loweralkyl, lower halogenated alkyl, lower substituted alkyl, lower alkenyl,lower halogenated alkenyl, lower substituted alkenyl, lower alkynyl,lower halogenated alkynyl, or lower substituted alkynyl.

[0146] Another group of compounds of Formula I includes any one or moreor any combination of the following in a smaller group of compounds ofthe following as the free base or a pharmaceutically acceptable saltthereof:

[0147] N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamide;

[0148] N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-5-carboxamide;

[0149]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1-benzofuran-6-carboxamide;

[0150]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1-benzofuran-5-carboxamide;

[0151]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyano-1-benzofuran-6-carboxamide;

[0152]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyano-1-benzofuran-5-carboxamide;

[0153]N-6-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2,6-dicarboxamide;

[0154]N-5-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2,5-dicarboxamide;

[0155]2-acetyl-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamide;

[0156]2-acetyl-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-5-carboxamide;

[0157]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-formyl-1-benzofuran-6-carboxamide;

[0158]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-formyl-1-benzofuran-5-carboxamide;

[0159]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-benzofuran-6-carboxamide;

[0160]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-benzofuran-5-carboxamide;

[0161]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-isopropyl-1-benzofuran-6-carboxamide;

[0162]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-isopropyl-1-benzofuran-5-carboxamide;

[0163]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-chloro-1-benzofuran-6-carboxamide;

[0164]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-chloro-1-benzofuran-5-carboxamide;

[0165]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-6-carboxamide;

[0166]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-5-carboxamide;

[0167]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethynyl-1-benzofuran-6-carboxamide;

[0168]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethynyl-1-benzofuran-5-carboxamide;

[0169]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-6-carboxamide;

[0170]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-5-carboxamide;

[0171]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-benzofuran-6-carboxamide;

[0172]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-benzofuran-5-carboxamide;

[0173]N-6-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-3,6-dicarboxamide;

[0174]N-5-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-3,5-dicarboxamide;

[0175]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-6-carboxamide;

[0176]N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-5-carboxamide;

[0177] N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indole-6-carboxamide;

[0178] N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1H-indole-5-carboxamide; anyof which is optionally substituted on the C-2 of quinuclidine withmethyl in the S configuration, for example but not limitation, to giveN-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamide.

[0179] Another group of compounds of Formula I includes any one or moreor any combination of the following in a smaller group of compounds ofthe following as the free base or a pharmaceutically acceptable saltthereof:

[0180]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-6-carboxamide;

[0181]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-5-carboxamide;

[0182]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-methyl-1-benzofuran-6-carboxamide;

[0183]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-methyl-1-benzofuran-5-carboxamide;

[0184]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-cyano-1-benzofuran-6-carboxamide;

[0185]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-cyano-1-benzofuran-5-carboxamide;

[0186]N-6-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-2,6-dicarboxamide;

[0187]N-5-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-2,5-dicarboxamide;

[0188]2-acetyl-N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-6-carboxamide;

[0189]2-acetyl-N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-5-carboxamide;

[0190]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-formyl-1-benzofuran-6-carboxamide;

[0191]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-formyl-1-benzofuran-5-carboxamide;

[0192]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-methyl-1-benzofuran-6-carboxamide;

[0193]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-methyl-1-benzofuran-5-carboxamide;

[0194]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-isopropyl-1-benzofuran-6-carboxamide;

[0195]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-isopropyl-1-benzofuran-5-carboxamide;

[0196]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-chloro-1-benzofuran-6-carboxamide;

[0197]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-chloro-1-benzofuran-5-carboxamide;

[0198]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-bromo-1-benzofuran-6-carboxamide;

[0199]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-bromo-1-benzofuran-5-carboxamide;

[0200]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-ethynyl-1-benzofuran-6-carboxamide;

[0201]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-ethynyl-1-benzofuran-5-carboxamide;

[0202]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-prop-1-ynyl-1-benzofuran-6-carboxamide;

[0203]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-prop-1-ynyl-1-benzofuran-5-carboxamide;

[0204]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-cyano-1-benzofuran-6-carboxamide;

[0205]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-cyano-1-benzofuran-5-carboxamide;

[0206]N-6-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-3,6-dicarboxamide;

[0207]N-5-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-3,5-dicarboxamide;

[0208]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzothiophene-6-carboxamide;

[0209]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzothiophene-5-carboxamide;

[0210]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1H-indole-6-carboxamide;

[0211]N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1H-indole-5-carboxamide;

[0212]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-6-carboxamide;

[0213]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-5-carboxamide;

[0214]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1-benzofuran-6-carboxamide;

[0215]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1-benzofuran-5-carboxamide;

[0216]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-cyano-1-benzofuran-6-carboxamide;

[0217] N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)]-2-cyano-1-benzofuran-5-carboxamide;

[0218]N-6-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-2,6-dicarboxamide;

[0219]N-5-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-2,5-dicarboxamide;

[0220]2-acetyl-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-6-carboxamide;

[0221]2-acetyl-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-5-carboxamide;

[0222]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-formyl-1-benzofuran-6-carboxamide;

[0223]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-formyl-1-benzofuran-5-carboxamide;

[0224]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-methyl-1-benzofuran-6-carboxamide;

[0225]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-methyl-1-benzofuran-5-carboxamide;

[0226]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-isopropyl-1-benzofuran-6-carboxamide;

[0227]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-isopropyl-1-benzofuran-5-carboxamide;

[0228]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-chloro-1-benzofuran-6-carboxamide;

[0229]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-chloro-1-benzofuran-5-carboxamide;

[0230]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-bromo-1-benzofuran-6-carboxamide;

[0231]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-bromo-1-benzofuran-5-carboxamide;

[0232]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-ethynyl-1-benzofuran-6-carboxamide;

[0233]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-ethynyl-1-benzofuran-5-carboxamide;

[0234]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-6-carboxamide;

[0235]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-5-carboxamide;

[0236]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-cyano-1-benzofuran-6-carboxamide;

[0237]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-cyano-1-benzofuran-5-carboxamide;

[0238]N-6-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-3,6-dicarboxamide;

[0239]N-5-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-3,5-dicarboxamide;

[0240]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzothiophene-6-carboxamide;

[0241]N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzothiophene-5-carboxamide;

[0242] N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1H-indole-6-carboxamide;

[0243] N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1H-indole-5-carboxamide;

[0244] N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-6-carboxamide;

[0245] N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-5-carboxamide;

[0246]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-methyl-1-benzofuran-6-carboxamide;

[0247]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-methyl-1-benzofuran-5-carboxamide;

[0248]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-cyano-1-benzofuran-6-carboxamide;

[0249]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-cyano-1-benzofuran-5-carboxamide;

[0250]N-6-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-2,6-dicarboxamide;

[0251]N-5-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-2,5-dicarboxamide;

[0252]2-acetyl-N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-6-carboxamide;

[0253]2-acetyl-N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-5-carboxamide;

[0254]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-formyl-1-benzofuran-6-carboxamide;

[0255]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-formyl-1-benzofuran-5-carboxamide;

[0256]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-methyl-1-benzofuran-6-carboxamide;

[0257]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-methyl-1-benzofuran-5-carboxamide;

[0258]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-isopropyl-1-benzofuran-6-carboxamide;

[0259]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-isopropyl-1-benzofuran-5-carboxamide;

[0260]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-chloro-1-benzofuran-6-carboxamide;

[0261]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-chloro-1-benzofuran-5-carboxamide;

[0262]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-bromo-1-benzofuran-6-carboxamide;

[0263]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-bromo-1-benzofuran-5-carboxamide;

[0264]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-ethynyl-1-benzofuran-6-carboxamide;

[0265]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-ethynyl-1-benzofuran-5-carboxamide;

[0266]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-prop-1-ynyl-1-benzofuran-6-carboxamide;

[0267]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-prop-1-ynyl-1-benzofuran-5-carboxamide;

[0268]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-cyano-1-benzofuran-6-carboxamide;

[0269]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-cyano-1-benzofuran-5-carboxamide;

[0270]N-6-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-3,6-dicarboxamide;

[0271]N-5-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-3,5-dicarboxamide;

[0272]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzothiophene-6-carboxamide;

[0273]N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzothiophene-5-carboxamide;

[0274] N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1H-indole-6-carboxamide;

[0275] N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1H-indole-5-carboxamide;

[0276] N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-6-carboxamide;

[0277] N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-5-carboxamide;

[0278]N-(2-azabicyclo[2.2.1]hept-5-yl)-2-methyl-1-benzofuran-6-carboxamide;

[0279]N-(2-azabicyclo[2.2.1]hept-5-yl)-2-methyl-1-benzofuran-5-carboxamide;

[0280]N-(2-azabicyclo[2.2.1]hept-5-yl)-2-cyano-1-benzofuran-6-carboxamide;

[0281]N-(2-azabicyclo[2.2.1]hept-5-yl)-2-cyano-1-benzofuran-5-carboxamide;

[0282]N-6-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-2,6-dicarboxamide;

[0283]N-5-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-2,5-dicarboxamide;

[0284]2-acetyl-N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-6-carboxamide;

[0285]2-acetyl-N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-5-carboxamide;

[0286]N-(2-azabicyclo[2.2.1]hept-5-yl)-2-formyl-1-benzofuran-6-carboxamide;

[0287]N-(2-azabicyclo[2.2.1]hept-5-yl)-2-formyl-1-benzofuran-5-carboxamide;

[0288]N-(2-azabicyclo[2.2.1]hept-5-yl)-3-methyl-1-benzofuran-6-carboxamide;

[0289]N-(2-azabicyclo[2.2.1]hept-5-yl)-3-methyl-1-benzofuran-5-carboxamide;

[0290]N-(2-azabicyclo[2.2.1]hept-5-yl)-3-isopropyl-1-benzofuran-6-carboxamide;

[0291]N-(2-azabicyclo[2.2.1]hept-5-yl)-3-isopropyl-1-benzofuran-5-carboxamide;

[0292]N-(2-azabicyclo[2.2.1]hept-5-yl)-3-chloro-1-benzofuran-6-carboxamide;

[0293]N-(2-azabicyclo[2.2.1]hept-5-yl)-3-chloro-1-benzofuran-5-carboxamide;

[0294]N-(2-azabicyclo[2.2.1]hept-5-yl)-3-bromo-1-benzofuran-6-carboxamide;

[0295]N-(2-azabicyclo[2.2.1]hept-5-yl)-3-bromo-1-benzofuran-5-carboxamide;

[0296]N-(2-azabicyclo[2.2.1]hept-5-yl)-3-ethynyl-1-benzofuran-6-carboxamide;

[0297]N-(2-azabicyclo[2.2.1]hept-5-yl)-3-ethynyl-1-benzofuran-5-carboxamide;

[0298]N-(2-azabicyclo[2.2.1]hept-5-yl)-3-prop-1-ynyl-1-benzofuran-6-carboxamide;

[0299]N-(2-azabicyclo[2.2.1]hept-5-yl)-3-prop-1-ynyl-1-benzofuran-5-carboxamide;

[0300]N-(2-azabicyclo[2.2.1]hept-5-yl)-3-cyano-1-benzofuran-6-carboxamide;

[0301]N-(2-azabicyclo[2.2.1]hept-5-yl)-3-cyano-1-benzofuran-5-carboxamide;

[0302]N-6-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-3,6-dicarboxamide;

[0303]N-5-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-3,5-dicarboxamide;

[0304] N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzothiophene-6-carboxamide;

[0305] N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzothiophene-5-carboxamide;

[0306] N-(2-azabicyclo[2.2.1]hept-5-yl)-1H-indole-6-carboxamide;

[0307] N-(2-azabicyclo[2.2.1]hept-5-yl)-1H-indole-5-carboxamide;

[0308] N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-6-carboxamide;

[0309] N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-5-carboxamide;

[0310]N-(2-azabicyclo[2.2.1]hept-6-yl)-2-methyl-1-benzofuran-6-carboxamide;

[0311]N-(2-azabicyclo[2.2.1]hept-6-yl)-2-methyl-1-benzofuran-5-carboxamide;

[0312]N-(2-azabicyclo[2.2.1]hept-6-yl)-2-cyano-1-benzofuran-6-carboxamide;

[0313]N-(2-azabicyclo[2.2.1]hept-6-yl)-2-cyano-1-benzofuran-5-carboxamide;

[0314]N-6-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-2,6-dicarboxamide;

[0315]N-5-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-2,5-dicarboxamide;

[0316]2-acetyl-N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-6-carboxamide;

[0317]2-acetyl-N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-5-carboxamide;

[0318]N-(2-azabicyclo[2.2.1]hept-6-yl)-2-formyl-1-benzofuran-6-carboxamide;

[0319]N-(2-azabicyclo[2.2.1]hept-6-yl)-2-formyl-1-benzofuran-5-carboxamide;

[0320]N-(2-azabicyclo[2.2.1]hept-6-yl)-3-methyl-1-benzofuran-6-carboxamide;

[0321]N-(2-azabicyclo[2.2.1]hept-6-yl)-3-methyl-1-benzofuran-5-carboxamide;

[0322]N-(2-azabicyclo[2.2.1]hept-6-yl)-3-isopropyl-1-benzofuran-6-carboxamide;

[0323]N-(2-azabicyclo[2.2.1]hept-6-yl)-3-isopropyl-1-benzofuran-5-carboxamide;

[0324]N-(2-azabicyclo[2.2.1]hept-6-yl)-3-chloro-1-benzofuran-6-carboxamide;

[0325]N-(2-azabicyclo[2.2.1]hept-6-yl)-3-chloro-1-benzofuran-5-carboxamide;

[0326]N-(2-azabicyclo[2.2.1]hept-6-yl)-3-bromo-1-benzofuran-6-carboxamide;

[0327]N-(2-azabicyclo[2.2.1]hept-6-yl)-3-bromo-1-benzofuran-5-carboxamide;

[0328]N-(2-azabicyclo[2.2.1]hept-6-yl)-3-ethynyl-1-benzofuran-6-carboxamide;

[0329]N-(2-azabicyclo[2.2.1]hept-6-yl)-3-ethynyl-1-benzofuran-5-carboxamide;

[0330]N-(2-azabicyclo[2.2.1]hept-6-yl)-3-prop-1-ynyl-1-benzofuran-6-carboxamide;

[0331]N-(2-azabicyclo[2.2.1]hept-6-yl)-3-prop-1-ynyl-1-benzofuran-5-carboxamide;

[0332]N-(2-azabicyclo[2.2.1]hept-6-yl)-3-cyano-1-benzofuran-6-carboxamide;

[0333]N-(2-azabicyclo[2.2.1]hept-6-yl)-3-cyano-1-benzofuran-5-carboxamide;

[0334]N-6-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-3,6-dicarboxamide;

[0335]N-5-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-3,5-dicarboxamide;

[0336] N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzothiophene-6-carboxamide;

[0337] N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzothiophene-5-carboxamide;

[0338] N-(2-azabicyclo[2.2.1]hept-6-yl)-1H-indole-6-carboxamide; or

[0339] N-(2-azabicyclo[2.2.1]hept-6-yl)-1H-indole-5-carboxamide.

[0340] The invention also concerns the synthesis of and isolation ofstereospecific intermediates and final compounds. Specifically, thepresent invention concerns the stereospecific synthesis of(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine, or salts thereof. Althoughthere are known procedures for making 1-azabicyclo[3.2.1]octan-3-amine,separation of the different stereoismers as described herein occurswithout using a chiral HPLC separation procedure. The procedure withinthis invention results in an efficient selective synthesis of(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine.

[0341] Another aspect of the present invention includes a method formaking (3R,5R)-1-azabicyclo[3.2.1]octan-3-amine or salt thereof. Oneprocess for producing (3R,5R)-1-azabicyclo[3.2.1]octan-3-amine or a saltthereof, from (3R)-methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate,comprises: the process of producing(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloridefrom (3R)-methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate;

[0342] the process of producing (5R)-1-azabicyclo[3.2.1]octan-3-one or asalt thereof from(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride;

[0343] and the process of producing(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine or a salt thereof from(5R)-1-azabicyclo[3.2.1]octan-3-one or a salt thereof.

[0344] Another process comprises: the process of producing (3R)-methyl1-[(S)-1-phenylethyl]pyrrolidine-3-acetate from(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine;

[0345] the process of producing(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloridefrom (3R)-methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate;

[0346] the process of producing (5R)-1-azabicyclo[3.2.1]octan-3-one or asalt thereof from(5R)-3-oxo-1-[(IS)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride;

[0347] and the process of producing(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine or a salt thereof from(5R)-1-azabicyclo[3.2.1]octan-3-one or a salt thereof.

[0348] Another process comprises: the process of producing(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid from(S)-(−)-α-methyl benzylamine;

[0349] the process of isolating(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid from aracemic mixture using a precipitating solvent without causing theprecipitation of other isomers, where the solvent can include a primaryalcohol, including but not limited to methanol;

[0350] the process of producing(3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine from(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid;

[0351] the process of producing(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)pyrrolidine from(3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine;

[0352] the process of producing(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine from(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)pyrrolidine;

[0353] the process of producing (3R)-methyl1-[(S)-1-phenylethyl]pyrrolidine-3-acetate from(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine;

[0354] the process of producing(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloridefrom (3R)-methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate;

[0355] the process of producing (5R)-1-azabicyclo[3.2.1]octan-3-one orsalt thereof from(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride;

[0356] and the process of producing(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine or salt thereof from(5R)-1-azabicyclo[3.2.1]octan-3-one or salt thereof.

[0357] Another process comprises: the process of producing(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid from(S)-(−)-α-methyl benzylamine;

[0358] the process of producing(3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine from(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid;

[0359] the process of producing(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)pyrrolidine from(3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine;

[0360] the process of producing(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine from(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)pyrrolidine;

[0361] the process of producing (3R)-methyl1-[(S)-1-phenylethyl]pyrrolidine-3-acetate from(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine;

[0362] the process of producing(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloridefrom (3R)-methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate;

[0363] the process of producing (5R)-1-azabicyclo[3.2.1]octan-3-one orsalt thereof from(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1 octane chloride;

[0364] and the process of producing(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine or salt thereof from(5R)-1-azabicyclo[3.2.1]octan-3-one or salt thereof.

[0365] The present invention also includes the compounds of the presentinvention, pharmaceutical compositions containing the active compounds,and methods to treat the identified diseases.

[0366] Further aspects and embodiments of the invention may becomeapparent to those skilled in the art from a review of the followingdetailed description, taken in conjunction with the examples and theappended claims. While the invention is susceptible of embodiments invarious forms, described hereafter are specific embodiments of theinvention with the understanding that the present disclosure is intendedas illustrative, and is not intended to limit the invention to thespecific embodiments described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0367] Surprisingly, we have found that compounds of Formula I:

[0368] wherein Azabicyclo is

[0369] R₁ is H, alkyl, halogenated alkyl, cycloalkyl, substitutedphenyl, or substituted naphthyl;

[0370] R₂ is H, F, Cl, Br, I, alkyl, halogenated alkyl, substitutedalkyl, cycloalkyl, or aryl;

[0371] k is 1 or 2, provided that when k is 2, each R₂ is other than H;

[0372] R₃ is H, lower alkyl, lower substituted alkyl, or lowerhalogenated alkyl;

[0373] W¹ is O, S, or N(R₁₅);

[0374] W⁵ and W⁶ are independently H or a bond to the carbonyl ofFormula I, provided that only one of W⁵ and W⁶ is said bond and theother is H;

[0375] Each R₄ is independently H, F, Cl, Br, I, alkyl, halogenatedalkyl, substituted alkyl, alkenyl, halogenated alkenyl, substitutedalkenyl, alkynyl, halogenated alkynyl, substituted alkynyl, cycloalkyl,halogenated cycloalkyl, substituted cycloalkyl, heterocycloalkyl,halogenated heterocyloalkyl, substituted heterocycloalkyl, lactamheterocylcoalkyl, phenyl, substituted phenyl, —OR₁₀, —SR₁₀, —SOR₁₀,—SO₂R₁₀, —NR₁₀C(O)R₅, —NR₁₀C(O)R₆, —NR₁₀C(O)R₈, —NR₁₀C(O)R₁₀, —N(R₁₀)₂,—NO₂, —C(O)R₁₀, —CN, —C(O)₂R₁₀, —C(O)NHR₁₀, —SCN, —S(O)NHR₁₀,—S(O)₂NHR₁₀, —NR₁₀S(O)₂R₁₀, R₅, or R₆, provided that when R₄ is—SO₁₋₂R₁₀ or —CO₁₋₂R₁₀ and R₁₀ is heterocycle, halogenated heterocycleor heterocycle substituted with 1 substitutent selected from R₁₃, acarbon in the heterocycle is bonded to the carbon or sulfur;

[0376] m is 1 or 2, provided that when m is 2 each R₄ is other than H;

[0377] R₅ is a 5-membered heteroaromatic mono-cyclic moiety containingwithin the ring 1-3 heteroatoms independently selected from the groupconsisting of —O—, ═N—, —N(R₁₆)—, and —S—, and having 0-1 substituentselected from R₉, and further having 0-3 substituents independentlyselected from F, Cl, Br, or I,

[0378] or R₅ is a 9-membered fused-ring moiety having a 6-membered ringfused to a 5-membered ring and having the formula

[0379] wherein each A is independently CR₁₄ or N, provided that only upto one A is N, E¹ and E² are independently selected from CR₁₄, O, S, orNR₁₆, and G is CR₁₄, provided that R₁₄ or R₁₆ can be a bond when—forms adouble bond and further provided that only one R₁₄ or R₁₆ can be a bondfor bonding R₅ to a moiety to which it is attached;

[0380] R₆ is a 6-membered heteroaromatic mono-cyclic moiety containingwithin the ring 1-3 heteroatoms selected from ═N— and having 0-1substituent selected from R₉ and 0-3 substituent(s) independentlyselected from F, Cl, Br, or I,

[0381] or R₆ is a 10-membered heteroaromatic bi-cyclic moiety containingwithin one or both rings 1-3 heteroatoms selected from ═N—, including,but not limited to, quinolinyl or isoquinolinyl, each 10-memberedfused-ring moiety having 0-1 substituent selected from R₉, and 0-3substituent(s) independently selected from F, Cl, Br, or I;

[0382] R₇ is H, alkyl, halogenated alkyl, substituted alkyl, cycloalkyl,halogenated cycloalkyl, substituted cycloalkyl, phenyl, or phenyl having0-4 substituents independently selected from F, Cl, Br, I, and R₉;

[0383] Each R₈ is independently H, alkyl, halogenated alkyl, substitutedalkyl, cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, phenyl, or phenyl substituted with 0-4 independentlyselected from F, Cl, Br, I, or R₉;

[0384] R₉ is alkyl, substituted alkyl, halogenated alky, —OR₁₁, —CN,—NO₂, —NR₁₀R₁₀;

[0385] Each R₁₀ is independently H, alkyl, cycloalkyl, heterocycloalkyl,alkyl substituted with 1 substituent selected from R₁₃, cycloalkylsubstituted with 1 substituent selected from R₁₃, heterocycloalkylsubstituted with 1 substituent selected from R₁₃, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, phenyl, orsubstituted phenyl;

[0386] Each R₁₁ is independently H, alkyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated cycloalkyl, or halogenatedheterocycloalkyl;

[0387] R₁₂ is —OR₁₁, —SR₁₁, alkyl, cycloalkyl, heterocycloalkyl,halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl,substituted alkyl, substituted cycloalkyl, substituted heterocycloalkyl,—N(R₁₁)₂, —C(O)R₁₁, —NO₂, —C(O)N(R₁₁)₂, —CN, —NR₁₁C(O)R₁₁,—S(O)₂N(R₁₁)₂, or —NR₁₁S(O)₂R₁₁;

[0388] R₁₃ is —OR₁₁, —SR₁₁, —N(R₁₁)₂, —C(O)R₁₁, —SOR₁₁, —SO₂R₁₁,—C(O)NR₁₁R₁₁, —CN, —CF₃, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂, —NR₁₁S(O)₂R₁₁, or—NO₂;

[0389] Each R₁₄ is independently bond, H, alkyl, cycloalkyl,heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenatedheterocycloalkyl, substituted alkyl, substituted cycloalkyl, substitutedheterocycloalkyl, —OR₁₁, —SR₁₁, —N(R₁₁)₂, —C(O)R₁₁, —NO₂, —C(O)N(R₁₁)₂,—CN, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂, —NR₁₁S(O)₂, R₁₁, F, Cl, Br, I, or abond, provided that the fused-ring moiety has 0-1 substituent selectedfrom alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenatedcycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substitutedcycloalkyl, substituted heterocycloalkyl, —OR₁₁, —SR₁₁, —N(R₁₁)₂,—C(O)R₁₁, —NO₂, —C(O)N(R₁₁)₂, —CN, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂, or—NR₁₁S(O)₂R₁₁, and further provided that the fused-ring moiety has 0-3substituent(s) selected from F, Cl, Br, or I;

[0390] R₁₅ is H, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, or substitutedheterocycloalkyl;

[0391] Each R₁₆ is indpendently bond, H, alkyl, halogenated alkyl,substituted alkyl, cycloalkyl, halogenated cycloalkyl, substitutedcycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl, orsubstituted heterocycloalkyl;

[0392] Aryl is phenyl, substituted phenyl, naphthyl, or substitutednaphthyl;

[0393] Substituted phenyl is a phenyl either having 1-4 substituentsindependently selected from F, Cl, Br, or I, or having 1 substituentselected from R₁₂ and 0-3 substituents independently selected from F,Cl, Br, or I;

[0394] Substituted naphthyl is a naphthalene moiety either having 1-4substituents independently selected from F, Cl, Br, or I, or having 1substituent selected from R₁₂ and 0-3 substituents independentlyselected from F, Cl, Br, or I, where the substitution can beindependently on either only one ring or both rings of said naphthalenemoiety;

[0395] Alkyl is both straight- and branched-chain moieties having from1-6 carbon atoms;

[0396] Lower alkyl is both straight- and branched-chain moieties havingfrom 1-4 carbon atoms;

[0397] Halogenated alkyl is an alkyl moiety having from 1-6 carbon atomsand having 1 to (2n+1) substituent(s) independently selected from F, Cl,Br, or I where n is the maximum number of carbon atoms in the moiety;

[0398] Lower halogenated alkyl is an alkyl moiety having from 1-4 carbonatoms and having 1 to (2n+1) substituent(s) independently selected fromF, Cl, Br, or I where n is the maximum number of carbon atoms in themoiety;

[0399] Substituted alkyl is an alkyl moiety from 1-6 carbon atoms andhaving 0-3 substituents independently selected from R₅, R₆, F, Cl, Br,or I and further having 1 substituent selected from —OR₁₀, —SR₁₀,—NR₁₀R₁₀, —C(O)R₁₀, —C(O)NR₁₀R₁₀, —CN, —NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀,—NR₁₀S(O)₂R₁₀, —NO₂, phenyl, or phenyl having 1 substituent selectedfrom R₉ and further having 0-3 substituents independently selected fromF, Cl, Br, or I;

[0400] Lower substituted alkyl is lower alkyl having 0-3 substituentsindependently selected from F, Cl, Br, or I, and further having 1substituent selected from —OR₁₀, —SR₁₀, —N(R₁₀)₂, —C(O)R₁₀,—C(O)N(R₁₀)₂, —CN, —NR₁₀C(O)R₁₀, —S(O)₂N(R₁₀)₂, —NR₁₀S(O)₂R₁₀, —NO₂,phenyl, R₅, or R₆,

[0401] wherein each R₁₀ is independently H, lower alkyl, cycloalkyl,heterocycloalkyl, or phenyl,

[0402] wherein any lower alkyl, cycloalkyl, heterocycloalkyl, or phenylis optionally substituted with up to two halogens independently selectedfrom F or Cl and up to one other substituent independently selected from—OR₁₁, —SR₁₁, —N(R₁₁)₂, —C(O)R₁₁, —C(O)N(R₁₁)₂, —CN, —CF₃, —NR₁₁C(O)R₁₁,—S(O)₂N(R₁₁)₂, —NR₁₁S(O)₂R₁₁, or —NO₂,

[0403] and wherein each R₁₁ is independently H, lower alkyl, lowercycloalkyl, heterocycloalkyl, lower halogenated alkyl, lower halogenatedcycloalkyl, or halogenated heterocycloalkyl;

[0404] Alkenyl is straight- and branched-chain moieties having from 2-6carbon atoms and having at least one carbon-carbon double bond;

[0405] Lower alkenyl is straight- and branched-chain moieties havingfrom 2-4 carbon atoms and having at least one carbon-carbon double bond;

[0406] Halogenated alkenyl is an unsaturated alkenyl moiety having from2-6 carbon atoms and having 1 to (2n−1) substituent(s) independentlyselected from F, Cl, Br, or I where n is the maximum number of carbonatoms in the moiety;

[0407] Lower halogenated alkenyl is an unsaturated alkenyl moiety havingfrom 2-4 carbon atoms and having 1 to (2n−1) substituent(s)independently selected from F, Cl, Br, or I where n is the maximumnumber of carbon atoms in the moiety;

[0408] Substituted alkenyl is an unsaturated alkenyl moiety having from2-6 carbon atoms and having 0-3 substituents independently selected fromF, or Cl, and further having 1 substituent selected from R₅, R₆, —OR₁₀,—SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —C(O)NR₁₀R₁₀, —NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀,—NR₁₀S(O)₂R₁₀, —CN, phenyl, or phenyl having 1 substituent selected fromR₉, and further having 0-3 substituents independently selected from F,Cl, Br, or I;

[0409] Lower substituted alkenyl is lower alkenyl having 0-3substituents independently selected from F, Cl, Br, or I, and furtherhaving 1 substituent selected from R₅, R₆, —CN, —OR₁₀, —SR₁₀, —N(R₁₀)₂,—C(O)R₁₀, —C(O)N(R₁₀)₂, —NR₁₀C(O)R₁₀, —S(O)₂N(R₁₀)₂, —NR₁₀S(O)₂R₁₀,—NO₂, phenyl, R₅, or R₆,

[0410] wherein each R₁₀ is independently H, lower alkyl, cycloalkyl,heterocycloalkyl, or phenyl,

[0411] wherein any lower alkyl, cycloalkyl, heterocycloalkyl, or phenylis optionally substituted with up to two halogens independently selectedfrom F or Cl and up to one other substituent independently selected from—OR₁₁, —SR₁₁, —N(R₁₁)₂, —C(O)R₁₁, —C(O)N(R₁₁)₂, —CN, —CF₃, —NR₁₁C(O)R₁₁,—S(O)₂N(R₁₁)₂, —NR₁₁S(O)₂R₁₀, or —NO₂,

[0412] and wherein each R₁₁ is independently H, lower alkyl, lowercycloalkyl, heterocycloalkyl, lower halogenated alkyl, lower halogenatedcycloalkyl, or halogenated heterocycloalkyl;

[0413] Alkynyl is straight- and branched-chained moieties having from2-6 carbon atoms and having at least one carbon-carbon triple bond;

[0414] Lower alkynyl is straight- and branched-chained moieties havingfrom 2-6 carbon atoms and having at least one carbon-carbon triple bond;

[0415] Halogenated alkynyl is an unsaturated alkynyl moiety having from3-6 carbon atoms and having 1 to (2n−3) substituent(s) independentlyselected from F, Cl, Br, or I where n is the maximum number of carbonatoms in the moiety;

[0416] Lower halogenated alkynyl is an unsaturated alkynyl moiety havingfrom 3-4 carbon atoms and having 1 to (2n−3) substituent(s)independently selected from F, Cl, Br, or I where n is the maximumnumber of carbon atoms in the moiety;

[0417] Substituted alkynyl is an unsaturated alkynyl moiety having from3-6 carbon atoms and having 0-3 substituents independently selected fromF, or Cl, and further having 1 substituent selected from R₅, R₆, —OR₁₀,—SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —C(O)NR₁₀R₁₀, —NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀,—NR₁₀S(O)₂R₁₀, —CN, phenyl, or phenyl having 1 substituent selected fromR₉, and further having 0-3 substituents independently selected from F,Cl, Br, or I;

[0418] Lower substituted alkynyl is lower alkynyl having 0-3substituents independently selected from F, or Cl, and further having 1substituent selected from R₅, R₆, —OR₁₀, —SR₁₀, —N(R₁₀)₂, —C(O)R₁₀,—C(O)N(R₁₀)₂, —CN, —NR₁₀C(O)R₁₀, —S(O)₂N(R₁₀)₂, —NR₁₀S(O)₂R₁₀, —NO₂,phenyl, R₅, or R₆,

[0419] wherein each R₁₀ is independently H, lower alkyl, cycloalkyl,heterocycloalkyl, or phenyl,

[0420] wherein any lower alkyl, cycloalkyl, heterocycloalkyl, or phenylis optionally substituted with up to two halogens independently selectedfrom F or Cl and up to one other substituent independently selected from—OR₁₀, —SR₁₁, —N(R₁₁)₂, —C(O)R₁₀, —C(O)N(R₁₁)₂, —CN, —CF₃, —NR₁₁C(O)R₁₁,—S(O)₂N(R₁₁,)₂, —NR₁₁S(O)₂R₁₁, or —NO₂,

[0421] and wherein each R₁₁ is independently H, lower alkyl, lowercycloalkyl, heterocycloalkyl, lower halogenated alkyl, lower halogenatedcycloalkyl, or halogenated heterocycloalkyl;

[0422] Cycloalkyl is a cyclic alkyl moiety having from 3-6 carbon atoms;

[0423] Halogenated cycloalkyl is a cyclic moiety having from 3-6 carbonatoms and having 1-4 substituents independently selected from F, or Cl;

[0424] Substituted cycloalkyl is a cyclic moiety having from 3-6 carbonatoms and having 0-3 substituents independently selected from F, or Cl,and further having 1 substituent selected from —OR₁₀, —SR₁₀, —NR₁₀R₁₀,—C(O)R₁₀, —CN, —C(O)NR₁₀R₁₀, —NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀,—NO₂, phenyl, or phenyl having 1 substituent selected from R₉, andfurther having 0-3 substituents independently selected from F, Cl, Br,or I;

[0425] Heterocycloalkyl is a cyclic moiety having 4-7 atoms with 1-2atoms within the ring being —S—, —N(R₇)—, or —O—;

[0426] Halogenated heterocycloalkyl is a cyclic moiety having from 4-7atoms with 1-2 atoms within the ring being —S—, —N(R₇)—, or —O—, andhaving 1-4 substituents independently selected from F, or Cl;

[0427] Substituted heterocycloalkyl is a cyclic moiety having from 4-7atoms with 1-2 atoms within the ring being —S—, —N(R₇)—, or —O— andhaving 0-3 substituents independently selected from —F, or —Cl, andfurther having 1 substituent selected from R₅, R₆, —OR₁₀, —SR₁₀,—NR₁₀R₁₀, —C(O)R₁₀, —C(O)NR₁₀R₁₀, —CN, —NR₁₀C(O)R₁₀, —NO₂,—S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀, phenyl, or phenyl having 1 substituentselected from R₉ and further having 0-3 substituents independentlyselected from F, Cl, Br, or I;

[0428] Lactam heterocycloalkyl is a cyclic moiety having from 4-7 atomswith one atom being only nitrogen with the bond to the lactamheterocycloalkyl thru said atom being only nitrogen and having a ═O on acarbon adjacent to said nitrogen, and having up to 1 additional ringatom being oxygen, sulfur, or nitrogen and further having 0-2substituents selected from F, Cl, Br, I, or R₉ where valency allows;

[0429] or pharmaceutical composition, pharmaceutically acceptable salt,racemic mixture, or pure enantiomer thereof useful to treat any one ofor combination of cognitive and attention deficit symptoms ofAlzheimer's, neurodegeneration associated with diseases such asAlzheimer's disease, pre-senile dementia (mild cognitive impairment),senile dementia, schizophrenia, psychosis, attention deficit disorder,attention deficit hyperactivity disorder, mood and affective disorders,amyotrophic lateral sclerosis, borderline personality disorder,traumatic brain injury, behavioral and cognitive problems associatedwith brain tumors, AIDS dementia complex, dementia associated withDown's syndrome, dementia associated with Lewy Bodies, Huntington'sdisease, depression, general anxiety disorder, age-related maculardegeneration, Parkinson's disease, tardive dyskinesia, Pick's disease,post traumatic stress disorder, dysregulation of food intake includingbulemia and anorexia nervosa, withdrawal symptoms associated withsmoking cessation and dependant drug cessation, Gilles de la Tourette'sSyndrome, glaucoma, neurodegeneration associated with glaucoma, orsymptoms associated with pain.

[0430] In another aspect, the invention includes methods of treating amammal suffering from schizophrenia or psychosis by administeringcompounds of Formula I in conjunction with antipsychotic drugs. Thecompounds of Formula I and the antipsychotic drugs can be administeredsimultaneously or at separate intervals. When administeredsimultaneously the compounds of Formula I and the antipsychotic drugscan be incorporated into a single pharmaceutical composition.Alternatively, two separate compositions, i.e., one containing compoundsof Formula I and the other containing antipsychotic drugs, can beadministered simultaneously.

[0431] The present invention also includes the intermediates, theprocesses to make them and the active compounds of Formula I,pharmaceutical compositions including the active compounds, and methodsto treat the identified diseases.

[0432] Abbreviations which are well known to one of ordinary skill inthe art may be used (e.g., “Ph” for phenyl, “Me” for methyl, “Et” forethyl, “h” or “hr” for hour or hours, min for minute or minutes, and“rt” or “RT” for room temperature).

[0433] All temperatures are in degrees Centigrade.

[0434] Room temperature is within the range of 15-25 degrees Celsius.

[0435] AChR refers to acetylcholine receptor.

[0436] nAChR refers to nicotinic acetylcholine receptor.

[0437] Pre-senile dementia is also known as mild cognitive impairment.

[0438] 5HT₃R refers to the serotonin-type 3 receptor.

[0439] α-btx refers to α-bungarotoxin.

[0440] FLIPR refers to a device marketed by Molecular Devices, Inc.designed to precisely measure cellular fluorescence in a high throughputwhole-cell assay. (Schroeder et. al., J. Biomolecular Screening, 1(2), p75-80, 1996).

[0441] TLC refers to thin-layer chromatography.

[0442] HPLC refers to high pressure liquid chromatography.

[0443] MeOH refers to methanol.

[0444] EtOH refers to ethanol.

[0445] IPA refers to isopropyl alcohol.

[0446] THF refers to tetrahydrofuran.

[0447] DMSO refers to dimethylsulfoxide.

[0448] DMF refers to N,N-dimethylformamide.

[0449] EtOAc refers to ethyl acetate.

[0450] TMS refers to tetramethylsilane.

[0451] TEA refers to triethylamine.

[0452] DIEA refers to N,N-diisopropylethylamine.

[0453] DIA refers to diisopropylamine.

[0454] MLA refers to methyllycaconitine.

[0455] Ether refers to diethyl ether.

[0456] HATU refers toO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate.

[0457] DBU refers to 1,8-diazobicyclo[5.4.0]undec-7-one.

[0458] CDI refers to carbonyl diimidazole.

[0459] NMO refers to N-methylmorpholine-N-oxide.

[0460] TPAP refers to tetrapropylammonium perruthenate.

[0461] Halogen is F, Cl, Br, or I.

[0462] Na₂SO₄ refers to sodium sulfate.

[0463] K₂CO₃ refers to potassium carbonate.

[0464] MgSO₄ refers to magnesium sulfate.

[0465] When Na₂SO₄, K₂CO₃, or MgSO₄ is used as a drying agent, it isanhydrous.

[0466] The carbon atom content of various hydrocarbon-containingmoieties is indicated by a prefix designating the minimum and maximumnumber of carbon atoms in the moiety, i.e., the prefix C_(i-j) indicatesa moiety of the integer “i” to the integer “j” carbon atoms, inclusive.Thus, for example, C₁₋₆ alkyl refers to alkyl of one to six carbonatoms.

[0467] Non-inclusive examples of heteroaryl compounds that fall withinthe definition of R₅ and R₆ include, but are not limited to, thienyl,benzothienyl, pyridyl, thiazolyl, quinolyl, pyrazinyl, pyrimidyl,imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl,benzisothiazolyl, benzisoxazolyl, benzimidazolyl, indolyl, benzoxazolyl,pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl, pyrrolyl,isoquinolinyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl,pydridazinyl, triazinyl, isoindolyl, purinyl, oxadiazolyl, furazanyl,benzofurazanyl, benzothiophenyl, benzothiazolyl, quinazolinyl,quinoxalinyl, naphthridinyl, and furopyridinyl.

[0468] Non-inclusive examples of heterocycloalkyl include, but are notlimited to, tetrahydrofurano, tetrahydropyrano, morpholino, pyrrolidino,piperidino, piperazine, azetidino, azetidinono, oxindolo,dihydroimidazolo, and pyrrolidinono

[0469] Mammal denotes human and other mammals.

[0470] Brine refers to an aqueous saturated sodium chloride solution.

[0471] Equ means molar equivalents.

[0472] IR refers to infrared spectroscopy.

[0473] Lv refers to leaving groups within a molecule, including Cl, OH,or mixed anhydride.

[0474] NMR refers to nuclear (proton) magnetic resonance spectroscopy,chemical shifts are reported in ppm (δ) downfield from TMS.

[0475] MS refers to mass spectrometry expressed as m/e or mass/chargeunit. HRMS refers to high resolution mass spectrometry expressed as m/eor mass/charge unit. [M+H]⁺ refers to an ion composed of the parent plusa proton. [M−H]⁻ refers to an ion composed of the parent minus a proton.[M+Na]⁺ refers to an ion composed of the parent plus a sodium ion.[M+K]⁺ refers to an ion composed of the parent plus a potassium ion. EIrefers to electron impact. ESI refers to electrospray ionization. CIrefers to chemical ionization. FAB refers to fast atom bombardment.

[0476] Amino protecting group includes, but is not limited to,carbobenzyloxy (CBz), tert butoxy carbonyl (BOC) and the like. Examplesof other suitable amino protecting groups are known to person skilled inthe art and can be found in “Protective Groups in Organic synthesis,”3rd Edition, authored by Theodora Greene and Peter Wuts.

[0477] Compounds of the present invention may be in the form ofpharmaceutically acceptable salts. The term “pharmaceutically acceptablesalts” refers to salts prepared from pharmaceutically acceptablenon-toxic bases including inorganic bases and organic bases, and saltsprepared from inorganic acids, and organic acids. Salts derived frominorganic bases include aluminum, ammonium, calcium, ferric, ferrous,lithium, magnesium, potassium, sodium, zinc, and the like. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, and the like. Salts derived from inorganic acids includesalts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuricacid, phosphoric acid, phosphorous acid and the like. Salts derived frompharmaceutically acceptable organic non-toxic acids include salts ofC₁₋₆ alkyl carboxylic acids, di-carboxylic acids, and tri-carboxylicacids such as acetic acid, propionic acid, fumaric acid, succinic acid,tartaric acid, maleic acid, adipic acid, and citric acid, and aryl andalkyl sulfonic acids such as toluene sulfonic acids and the like.

[0478] By the term “effective amount” of a compound as provided hereinis meant a nontoxic but sufficient amount of the compound(s) to providethe desired effect. As pointed out below, the exact amount required willvary from subject to subject, depending on the species, age, and generalcondition of the subject, the severity of the disease that is beingtreated, the particular compound(s) used, the mode of administration,and the like. Thus, it is not possible to specify an exact “effectiveamount.” However, an appropriate effective amount may be determined byone of ordinary skill in the art using only routine experimentation.

[0479] The amount of therapeutically effective compound(s) that isadministered and the dosage regimen for treating a disease conditionwith the compounds and/or compositions of this invention depends on avariety of factors, including the age, weight, sex and medical conditionof the subject, the severity of the disease, the route and frequency ofadministration, and the particular compound(s) employed, and thus mayvary widely. The compositions contain well know carriers and excipientsin addition to a therapeutically effective amount of compounds ofFormula I. The pharmaceutical compositions may contain active ingredientin the range of about 0.001 to 100 mg/kg/day for an adult, preferably inthe range of about 0.1 to 50 mg/kg/day for an adult. A total daily doseof about 1 to 1000 mg of active ingredient may be appropriate for anadult. The daily dose can be administered in one to four doses per day.

[0480] In addition to the compound(s) of Formula I, the composition fortherapeutic use may also comprise one or more non-toxic,pharmaceutically acceptable carrier materials or excipients. The term“carrier” material or “excipient” herein means any substance, not itselfa therapeutic agent, used as a carrier and/or diluent and/or adjuvant,or vehicle for delivery of a therapeutic agent to a subject or added toa pharmaceutical composition to improve its handling or storageproperties or to permit or facilitate formation of a dose unit of thecomposition into a discrete article such as a capsule or tablet suitablefor oral administration. Excipients can include, by way of illustrationand not limitation, diluents, disintegrants, binding agents, adhesives,wetting agents, polymers, lubricants, glidants, substances added to maskor counteract a disagreeable taste or odor, flavors, dyes, fragrances,and substances added to improve appearance of the composition.Acceptable excipients include lactose, sucrose, starch powder, celluloseesters of alkanoic acids, cellulose alkyl esters, talc, stearic acid,magnesium stearate, magnesium oxide, sodium and calcium salts ofphosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate,polyvinyl-pyrrolidone, and/or polyvinyl alcohol, and then tableted orencapsulated for convenient administration. Such capsules or tablets maycontain a controlled-release formulation as may be provided in adispersion of active compound in hydroxypropyl-methyl cellulose, orother methods known to those skilled in the art. For oraladministration, the pharmaceutical composition may be in the form of,for example, a tablet, capsule, suspension or liquid. If desired, otheractive ingredients may be included in the composition.

[0481] In addition to the oral dosing, noted above, the compositions ofthe present invention may be administered by any suitable route, in theform of a pharmaceutical composition adapted to such a route, and in adose effective for the treatment intended. The compositions may, forexample, be administered parenterally, e.g., intravascularly,intraperitoneally, subcutaneously, or intramuscularly. For parenteraladministration, saline solution, dextrose solution, or water may be usedas a suitable carrier. Formulations for parenteral administration may bein the form of aqueous or non-aqueous isotonic sterile injectionsolutions or suspensions. These solutions and suspensions may beprepared from sterile powders or granules having one or more of thecarriers or diluents mentioned for use in the formulations for oraladministration. The compounds may be dissolved in water, polyethyleneglycol, propylene glycol, EtOH, corn oil, cottonseed oil, peanut oil,sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.Other adjuvants and modes of administration are well and widely known inthe pharmaceutical art.

[0482] The serotonin type 3 receptor (5HT₃R) is a member of asuperfamily of ligand-gated ion channels, which includes the muscle andneuronal nAChR, the glycine receptor, and the γ-aminobutyric acid type Areceptor. Like the other members of this receptor superfamily, the 5HT₃Rexhibits a large degree of sequence homology with α7 nAChR butfunctionally the two ligand-gated ion channels are very different. Forexample, α7 nAChR is rapidly inactivated, is highly permeable to calciumand is activated by acetylcholine and nicotine. On the other hand, 5HT₃Ris inactivated slowly, is relatively impermeable to calcium and isactivated by serotonin. These experiments suggest that the α7 nAChR and5HT₃R proteins have some degree of homology, but function verydifferently. Indeed the pharmacology of the channels is very different.For example, Ondansetron, a highly selective 5HT₃R antagonist, haslittle activity at the α7 nAChR. The converse is also true. For example,GTS-21, a highly selective α7 nAChR agonist, has little activity at the5HT₃R.

[0483] α7 nAChR is a ligand-gated Ca⁺⁺ channel formed by a homopentamerof α7 subunits. Previous studies have established that α-bungarotoxin(α-btx) binds selectively to this homopetameric, α7 nAChR subtype, andthat α7 nAChR has a high affinity binding site for both α-btx andmethyllycaconitine (MLA). α7 nAChR is expressed at high levels in thehippocampus, ventral tegmental area and ascending cholinergicprojections from nucleus basilis to thalamocortical areas. α7 nAChRagonists increase neurotransmitter release, and increase cognition,arousal, attention, learning and memory.

[0484] Data from human and animal pharmacological studies establish thatnicotinic cholinergic neuronal pathways control many important aspectsof cognitive function including attention, learning and memory (Levin,E. D., Psychopharmacology, 108:417-31, 1992; Levin, E. D. and Simon B.B., Psychopharmacology, 138:217-30, 1998). For example, it is well knownthat nicotine increases cognition and attention in humans. ABT-418, acompound that activates α4β2 and (α7 nAChR, improves cognition andattention in clinical trials of Alzheimer's disease andattention-deficit disorders (Potter, A. et. al., Psychopharmacology(Berl)., 142(4):334-42, Mar. 1999; Wilens, T. E. et. al., Am. J.Psychiatry, 156(12):1931-7, Dec. 1999). It is also clear that nicotineand selective but weak (α7 nAChR agonists increase cognition andattention in rodents and non-human primates.

[0485] Schizophrenia is a complex multifactorial illness caused bygenetic and non-genetic risk factors that produce a constellation ofpositive and negative symptoms. The positive symptoms include delusionsand hallucinations and the negative symptoms include deficits in affect,attention, cognition and information processing. No single biologicalelement has emerged as a dominant pathogenic factor in this disease.Indeed, it is likely that schizophrenia is a syndrome that is producedby the combination of many low penetrance risk factors. Pharmacologicalstudies established that dopamine receptor antagonists are efficaciousin treating the overt psychotic features (positive symptoms) ofschizophrenia such as hallucinations and delusions. Clozapine, an“atypical” antipsychotic drug, is novel because it is effective intreating both the positive and some of the negative symptoms of thisdisease. Clozapine's utility as a drug is greatly limited becausecontinued use leads to an increased risk of agranulocytosis and seizure.No other antipsychotic drug is effective in treating the negativesymptoms of schizophrenia. This is significant because the restorationof cognitive functioning is the best predictor of a successful clinicaland functional outcome of schizophrenic patients (Green, M. F., Am JPsychiatry, 153:321-30, 1996). By extension, it is clear that betterdrugs are needed to treat the cognitive disorders of schizophrenia inorder to restore a better state of mental health to patients with thisdisorder.

[0486] One aspect of the cognitive deficit of schizophrenia can bemeasured by using the auditory event-related potential (P50) test ofsensory gating. In this test, electroencepholographic (EEG) recordingsof neuronal activity of the hippocampus are used to measure thesubject's response to a series of auditory “clicks” (Adler, L. E. et.al., Biol. Psychiatry, 46:8-18, 1999). Normal individuals respond to thefirst click with greater degree than to the second click. In general,schizophrenics and schizotypal patients respond to both clicks nearlythe same (Cullum, C. M. et. al., Schizophr. Res., 10:131-41, 1993).These data reflect a schizophrenic's inability to “filter” or ignoreunimportant information. The sensory gating deficit appears to be one ofthe key pathological features of this disease (Cadenhead, K. S. et. al.,Am. J. Psychiatry, 157:55-9, 2000). Multiple studies show that nicotinenormalizes the sensory deficit of schizophrenia (Adler, L. E. et. al.,Am. J. Psychiatry, 150:1856-61, 1993). Pharmacological studies indicatethat nicotine's effect on sensory gating is via the α7 nAChR (Adler, L.E. et. al., Schizophr. Bull., 24:189-202, 1998). Indeed, the biochemicaldata indicate that schizophrenics have 50% fewer of α7 nAChR receptorsin the hippocampus, thus giving a rationale to partial loss of α7 nAChRfunctionality (Freedman, R. et. al., Biol. Psychiatry, 38:22-33, 1995).Interestingly, genetic data indicate that a polymorphism in the promoterregion of the α7 nAChR gene is strongly associated with the sensorygating deficit in schizophrenia (Freedman, R. et. al., Proc. Nat'l Acad.Sci. USA, 94(2):587-92, 1997; Myles-Worsley, M. et. al., Am. J. Med.Genet, 88(5):544-50, 1999). To date, no mutation in the coding region ofthe α7 nAChR has been identified. Thus, schizophrenics express the sameα7 nAChR as non-schizophrenics.

[0487] Selective α7 nAChR agonists may be found using a functional assayon FLIPR (see WO 00/73431 A2). FLIPR is designed to read the fluorescentsignal from each well of a 96 or 384 well plate as fast as twice asecond for up to 30 minutes. This assay may be used to accuratelymeasure the functional pharmacology of α7 nAChR and 5HT₃R. To conductsuch an assay, one uses cell lines that expressed functional forms ofthe α7 nAChR using the a7/5-HT₃ channel as the drug target and celllines that expressed functional 5HT₃R. In both cases, the ligand-gatedion channel was expressed in SH-EP1 cells. Both ion channels can producerobust signal in the FLIPR assay.

[0488] The compounds of the present invention are α7 nAChR agonists andmay be used to treat a wide variety of diseases. For example, they maybe used in treating schizophrenia, or psychosis.

[0489] Schizophrenia is a disease having multiple aspects. Currentlyavailable drugs are generally aimed at controlling the positive aspectsof schizophrenia, such as delusions. One drug, Clozapine, is aimed at abroader spectrum of symptoms associated with schizophrenia. This drughas many side effects and is thus not suitable for many patients. Thus,there is a need for a drug to treat the cognitive and attention deficitsassociated with schizophrenia. Similarly, there is a need for a drug totreat the cognitive and attention deficits associated withschizoaffective disorders, or similar symptoms found in the relatives ofschizophrenic patients.

[0490] Psychosis is a mental disorder characterized by gross impairmentin the patient's perception of reality. The patient may suffer fromdelusions, and hallucinations, and may be incoherent in speech. Hisbehavior may be agitated and is often incomprehensible to those aroundhim. In the past, the term psychosis has been applied to many conditionsthat do not meet the stricter definition given above. For example, mooddisorders were named as psychoses.

[0491] There are a variety of antipsychotic drugs. The conventionalantipsychotic drugs include Chlorpromazine, Fluphenazine, Haloperidol,Loxapine, Mesoridazine, Molindone, Perphenazine, Pimozide, Thioridazine,Thiothixene, and Trifluoperazine. These drugs all have an affinity forthe dopamine 2 receptor.

[0492] These conventional antipsychotic drugs have several side effects,including sedation, weight gain, tremors, elevated prolactin levels,akathisia (motor restlessness), dystonia and muscle stiffness. Thesedrugs may also cause tardive dyskinesia. Unfortunately, only about 70%of patients with schizophrenia respond to conventional antipsychoticdrugs. For these patients, atypical antipsychotic drugs are available.

[0493] Atypical antipsychotic drugs generally are able to alleviatepositive symptoms of psychosis while also improving negative symptoms ofthe psychosis to a greater degree than conventional antipsychotics.These drugs may improve neurocognitive deficits. Extrapyramidal (motor)side effects are not as likely to occur with the atypical antipsychoticdrugs, and thus, these atypical antipsychotic drugs have a lower risk ofproducing tardive dyskinesia. Finally these atypical antipsychotic drugscause little or no elevation of prolactin. Unfortunately, these drugsare not free of side effects. Although these drugs each producedifferent side effects, as a group the side effects include:agranulocytosis; increased risk of seizures, weight gain, somnolence,dizziness, tachycardia, decreased ejaculatory volume, and mildprolongation of QTc interval.

[0494] In a combination therapy to treat multiple symptoms of diseasessuch as schizophrenia, the compounds of Formula I and the anti-psychoticdrugs can be administered simultaneously or at separate intervals. Whenadministered simultaneously the compounds of Formula I and theanti-psychotic drugs can be incorporated into a single pharmaceuticalcomposition, e.g., a pharmaceutical combination therapy composition.Alternatively, two separate compositions, i.e., one containing compoundsof Formula I and the other containing anti-psychotic drugs, can beadministered simultaneously. Examples of anti-psychotic drugs, inaddition to those listed above, include, but are not limited to,Thorazine, Mellaril, Trilafon, Navane, Stelazine, Permitil, Prolixin,Risperdal, Zyprexa, Seroquel, ZELDOX, Acetophenazine, Carphenazine,Chlorprothixene, Droperidol, Loxapine, Mesoridazine, Molindone,Ondansetron, Pimozide, Prochlorperazine, and Promazine.

[0495] A pharmaceutical combination therapy composition can includetherapeutically effective amounts of the compounds of Formula I and atherapeutically effective amount of anti-psychotic drugs. Thesecompositions may be formulated with common excipients, diluents orcarriers, and compressed into tablets, or formulated elixirs orsolutions for convenient oral administration or administered byintramuscular intravenous routes. The compounds can be administeredrectally, topically, orally, sublingually, or parenterally and maybeformulated as sustained relief dosage forms and the like.

[0496] When separately administered, therapeutically effective amountsof compositions containing compounds of Formula I and anti-psychoticdrugs are administered on a different schedule. One may be administeredbefore the other as long as the time between the two administrationsfalls within a therapeutically effective interval. A therapeuticallyeffective interval is a period of time beginning when one of either (a)the compounds of Formula I, or (b) the anti-psychotic drugs isadministered to a human and ending at the limit of the beneficial effectin the treatment of schizophrenia or psychosis of the combination of (a)and (b). The methods of administration of the compounds of Formula I andthe anti-psychotic drugs may vary. Thus, either agent or both agents maybe administered rectally, topically, orally, sublingually, orparenterally.

[0497] As discussed, the compounds of the present invention are α7 nAChRagonists. Therefore, as another aspect of the present invention, thecompounds of the present invention may be used to treat a variety ofdiseases including cognitive and attention deficit symptoms ofAlzheimer's, neurodegeneration associated with diseases such asAlzheimer's disease, pre-senile dementia (also known as mild cognitiveimpairment), and senile dementia.

[0498] Alzheimer's disease has many aspects, including cognitive andattention deficits. Currently, these deficits are treated withcholinesterase inhibitors. These inhibitors slow the break down ofacetylcholine, and thereby provide a general nonspecific increase in theactivity of the cholinergic nervous system. Since the drugs arenonspecific, they have a wide variety of side effects. Thus, there is aneed for a drug that stimulates a portion of the cholinergic pathwaysand thereby provides improvement in the cognitive and attention deficitsassociated with Alzheimer's disease without the side effects created bynonspecific stimulation of the cholinergic pathways.

[0499] Neurodegeneration is a common problem associated with diseasessuch as Alzheimer's disease. While the current drugs treat some of thesymptoms of this disease, they do not control the underlying pathologyof the disease. Accordingly, it would be desirable to provide a drugthat can slow the progress of Alzheimer's disease.

[0500] Pre-senile dementia (mild cognitive impairment) concerns memoryimpairment rather than attention deficit problems and otherwiseunimpaired cognitive functioning. Mild cognitive impairment isdistinguished from senile dementia in that mild cognitive impairmentinvolves a more persistent and troublesome problem of memory loss forthe age of the patient. There currently is no medication specificallyidentified for treatment of mild cognitive impairment, due somewhat tothe newness of identifying the disease. Therefore, there is a need for adrug to treat the memory problems associated with mild cognitiveimpairment.

[0501] Senile dementia is not a single disease state. However, theconditions classified under this name frequently include cognitive andattention deficits. Generally, these deficits are not treated.Accordingly, there is a need for a drug that provides improvement in thecognitive and attention deficits associated with senile dementia.

[0502] As discussed, the compounds of the present invention are α7 nAChRagonists. Therefore, yet other diseases to be treated with compounds ofthe present invention include treating the cognitive and attentiondeficits as well as the neurodegeneration associated with any one ormore or combination of the following: attention deficit disorder,attention deficit hyperactivity disorder, depression, anxiety, generalanxiety disorder, post traumatic stress disorder, mood and affectivedisorders, amyotrophic lateral sclerosis, borderline personalitydisorder, traumatic brain injury, behavioral and cognitive problemsassociated with brain tumors, AIDS dementia complex, dementia associatedwith Down's syndrome, dementia associated with Lewy Bodies, Huntington'sdisease, Parkinson's disease, tardive dyskinesia, Pick's disease,dysregulation of food intake including bulemia and anorexia nervosa,withdrawal symptoms associated with smoking cessation and dependant drugcessation, Gilles de la Tourette's Syndrome, age-related maculardegeneration, glaucoma, neurodegeneration associated with glaucoma, orsymptoms associated with pain.

[0503] Attention deficit disorder is generally treated withmethylphenidate, an amphetamine-like molecule that has some potentialfor abuse. Accordingly, it would be desirable to provide a drug thattreats attention deficit disorder while having fewer side effects thanthe currently used drug.

[0504] Attention deficit hyperactivity disorder, otherwise known asADHD, is a neurobehavioral disorder affecting 3-5% of all Americanchildren. ADHD concerns cognitive alone or both cognitive and behavioralactions by interfering with a person's ability to stay on a task and toexercise age-appropriate inhibition. Several types of ADHD exist: apredominantly inattentive subtype, a predominantly hyperactive-impulsivesubtype, and a combined subtype. Treatment may include medications suchas methylphenidate, dextroamphetamine, or pemoline, which act todecrease impulsivity and hyperactivity and to increase attention. No“cure” for ADHD currently exists. Children with the disorder seldomoutgrow it; therefore, there is a need for appropriate medicaments.

[0505] Depression is a mood disorder of varying lengths of normallyseveral months to more than two years and of varying degrees of feelingsinvolving sadness, despair, and discouragement. The heterocyclicantidepressants (HCA's) are currently the largest class ofantidepressants, but monoamine oxidase inhibitors (MAOI's) are used inparticular types of depression. Common side effects from HCA's aresedation and weight gain. In elderly patients with organic braindisease, the side effects from HCA's can also include seizures andbehavioral symptoms. The main side effects from using MAOI's occur fromdietary and drug interactions. Therefore, agents with fewer side effectswould be useful.

[0506] Anxiety disorders (disorders with prominent anxiety or phobicavoidance), represent an area of umet medical needs in the treatment ofpsychiatric illness. See Diagnostic & Statistical Manual of MentalDisorders, IV (1994), pp 393-394, for various disease forms of anxiety.

[0507] General anxiety disorder (GAD) occurs when a person worries aboutthings such as family, health, or work when there is no reason to worryand is unable not to worry. About 3 to 4% of the U.S. population has GADduring the course of a year. GAD most often strikes people in childhoodor adolescence, but can begin in adulthood, too. It affects women moreoften than men. Currently, treatment involves cognitive-behavioraltherapy, relaxation techniques, and biofeedback to control muscletension and medications such as benzodiazepines, imipramine, andbuspirone. These drugs are effective but all have side-effectliabilities. Therefore, there is a need of a pharmaceutical agent toaddress the symptoms with fewer side effects.

[0508] Anxiety also includes post-traumatic stress disorder (PTSD),which is a form of anxiety triggered by memories of a traumatic eventthat directly affected the patient or that the patient may havewitnessed. The disorder commonly affects survivors of traumatic eventsincluding sexual assault, physical assault, war, torture, naturaldisasters, an automobile accident, an airplane crash, a hostagesituation, or a death camp. The affliction also can affect rescueworkers at an airplane crash or a mass shooting, someone who witnessed atragic accident or someone who has unexpectedly lost a loved one.Treatment for PTSD includes cognitive-behavioral therapy, grouppsychotherapy, and medications such as Clonazepam, Lorazepam andselective serotonin-reuptake inhibitors such as Fluoxetine, Sertraline,Paroxetine, Citalopram and Fluvoxamine. These medications help controlanxiety as well as depression. Various forms of exposure therapy (suchas systemic desensitization and imaginal flooding) have all been usedwith PTSD patients. Exposure treatment for PTSD involves repeatedreliving of the trauma, under controlled conditions, with the aim offacilitating the processing of the trauma. Therefore, there is a needfor better pharmaceutical agents to treat post traumatic stressdisorder.

[0509] Mood and affective disorders fall within a large group ofdiseases, including monopolar depression and bi-polar mood disorder.These diseases are treated with three major classes of compounds. Thefirst group is the heterocyclic antidepressant (HCA's). This groupincludes the well-known tricyclic antidepressants. The second group ofcompounds used to treat mood disorders is the monoamine oxidaseinhibitors (MAOI's) that are used in particular types of diseases. Thethird drug is lithium. Common side effects from HCA's are sedation andweight gain. In elderly patients with organic brain disease, the sideeffects of HCA's can also include seizures and behavioral symptoms. Themain side effects from using MAOI's occur from dietary and druginteractions. Benign side effects from the use of lithium include, butare not limited to, weight gain, nausea, diarrhea, polyuria, polydipsia,and tremor. Toxic side effects from lithium can include persistentheadache, mental confusion, and may reach seizures and cardiacarrhythmias. Therefore, agents with less side effects or interactionswith food or other medications would be useful.

[0510] Borderline personality disorder, although not as well known asbipolar disorder, is more common. People having borderline personalitydisorder suffer from a disorder of emotion regulation. Pharmaceuticalagents are used to treat specific symptoms, such as depression orthinking distortions.

[0511] Acquired immune deficiency syndrome (AIDS) results from aninfection with the human immunodeficiency virus (HIV). This virusattacks selected cells and impairs the proper function of the immune,nervous, and other systems. HIV infection can cause other problems suchas, but not limited to, difficulties in thinking, otherwise known asAIDS dementia complex. Therefore, there is a need to drugs to relievethe confusion and mental decline of persons with AIDS.

[0512] Amyotrophic lateral sclerosis, also known as Lou Gehrig'sdisease, belongs to a class of disorders known as motor neuron diseaseswherein specific nerve cells in the brain and spinal cord graduallydegenerate to negatively affect the control of voluntary movement.Currently, there is no cure for amyotrophic lateral sclerosis althoughpatients may receive treatment from some of their symptoms and althoughRiluzole has been shown to prolong the survival of patients. Therefore,there is a need for a pharmaceutical agent to treat this disease.

[0513] Traumatic brain injury occurs when the brain is damaged from asudden physical assault on the head. Symptoms of the traumatic braininjury include confusion and other cognitive problems. Therefore, thereis a need to address the symptoms of confusion and other cognitiveproblems.

[0514] Brain tumors are abnormal growths of tissue found inside of theskull. Symptoms of brain tumors include behavioral and cognitiveproblems. Surgery, radiation, and chemotherapy are used to treat thetumor, but other agents are necessary to address associated symptoms.Therefore, there is a need to address the symptoms of behavioral andcognitive problems.

[0515] Persons with Down's syndrome have in all or at least some oftheir cells an extra, critical portion of the number 21 chromosome.Adults who have Down's syndrome are known to be at risk forAlzheimer-type dementia. Currently, there is no proven treatment forDown's syndrome. Therefore, there is a need to address the dementiaassociated with Down's syndrome.

[0516] Genetically programmed degeneration of neurons in certain areasof the brain cause Huntington's disease. Early symptoms of Huntington'sdisease include mood swings, or trouble learning new things orremembering a fact. Most drugs used to treat the symptoms ofHuntington's disease have side effects such as fatigue, restlessness, orhyperexcitability. Currently, there is no treatment to stop or reversethe progression of Huntington's disease. Therefore, there is a need of apharmaceutical agent to address the symptoms with fewer side effects.

[0517] Dementia with Lewy Bodies is a neurodegenerative disorderinvolving abnormal structures known as Lewy bodies found in certainareas of the brain. Symptoms of dementia with Lewy bodies include, butare not limited to, fluctuating cognitive impairment with episodicdelirium. Currently, treatment concerns addressing the parkinsonian andpsychiatric symptoms. However, medicine to control tremors or loss ofmuscle movement may actually accentuate the underlying disease ofdementia with Lewy bodies. Therefore, there is a need of apharmaceutical agent to treat dementia with Lewy bodies.

[0518] Parkinson's disease is a neurological disorder characterized bytremor, hypokinesia, and muscular rigidity. Currently, there is notreatment to stop the progression of the disease. Therefore, there is aneed of a pharmaceutical agent to address Parkinson's.

[0519] Tardive dyskinesia is associated with the use of conventionalantipsychotic drugs. This disease is characterized by involuntarymovements most often manifested by puckering of the lips and tongueand/or writhing of the arms or legs. The incidence of tardive dyskinesiais about 5% per year of drug exposure among patients taking conventionalantipsychotic drugs. In about 2% of persons with the disease, tardivedyskinesia is severely disfiguring. Currently, there is no generalizedtreatment for tardive dyskinesia. Furthermore, the removal of theeffect-causing drugs is not always an option due to underlying problems.Therefore, there is a need for a pharmaceutical agent to address thesymptoms of tardive dyskinesia.

[0520] Pick's disease results from a slowly progressive deterioration ofsocial skills and changes in personality with the resulting symptomsbeing impairment of intellect, memory, and language. Common symptomsinclude memory loss, lack of spontaneity, difficulty in thinking orconcentrating, and speech disturbances. Currently, there is no specifictreatment or cure for Pick's disease but some symptoms can be treatedwith cholinergic and serotonin-boosting antidepressants. In addition,antipsychotic medications may alleviate symptoms in FTD patients who areexperiencing delusions or hallucinations. Therefore, there is a need fora pharmaceutical agent to treat the progressive deterioration of socialskills and changes in personality and to address the symptoms with fewerside effects.

[0521] Dysregulation of food intake associated with eating disease,including bulemia nervosa and anorexia nervosa, involveneurophysiological pathways. Anorexia nervosa is hard to treat due topatients not entering or remaining in after entering programs.Currently, there is no effective treatment for persons suffering fromsevere anorexia nervosa. Cognitive behavioral therapy has helpedpatients suffering from bulemia nervosa; however, the response rate isonly about 50% and current treatment does not adequately addressemotional regulation. Therefore, there is a need for pharmaceuticalagents to address neurophysiological problems underlying diseases ofdysregulation of food intake.

[0522] Cigarette smoking has been recognized as a major public healthproblem for a long time. However, in spite of the public awareness ofhealth hazard, the smoking habit remains extraordinarily persistent anddifficult to break. There are many treatment methods available, and yetpeople continue to smoke. Administration of nicotine transdermally, orin a chewing gum base is common treatments. However, nicotine has alarge number of actions in the body, and thus can have many sideeffects. It is clear that there is both a need and a demand of longstanding for a convenient and relatively easy method for aiding smokersin reducing or eliminating cigarette consumption. A drug that couldselectively stimulate only certain of the nicotinic receptors would beuseful in smoke cessation programs.

[0523] Smoke cessation programs may involve oral dosing of the drug ofchoice. The drug may be in the form of tablets. However, it is preferredto administer the daily dose over the waking hours, by administration ofa series of incremental doses during the day. The preferred method ofsuch administration is a slowly dissolving lozenge, troche, or chewinggum, in which the drug is dispersed. Another drug in treating nicotineaddiction is Zyban. This is not a nicotine replacement, as are the gumand patch. Rather, this works on other areas of the brain, and itseffectiveness is to help control nicotine craving or thoughts aboutcigarette use in people trying to quit. Zyban is not very effective andeffective drugs are needed to assist smokers in their desire to stopsmoking. These drugs may be administered transdermally through the useof skin patches. In certain cases, the drugs may be administered bysubcutaneous injection, especially if sustained release formulations areused.

[0524] Drug use and dependence is a complex phenomenon, which cannot beencapsulated within a single definition. Different drugs have differenteffects, and therefore different types of dependence. Drug dependencehas two basic causes, that is, tolerance and physical dependence.Tolerance exists when the user must take progressively larger doses toproduce the effect originally achieved with smaller doses. Physicaldependence exists when the user has developed a state of physiologicadaptation to a drug, and there is a withdrawal (abstinence) syndromewhen the drug is no longer taken. A withdrawal syndrome can occur eitherwhen the drug is discontinued or when an antagonist displaces the drugfrom its binding site on cell receptors, thereby counteracting itseffect. Drug dependence does not always require physical dependence.

[0525] In addition drug dependence often involves psychologicaldependence, that is, a feeling of pleasure or satisfaction when takingthe drug. These feelings lead the user to repeat the drug experience orto avoid the displeasure of being deprived of the drug. Drugs thatproduce strong physical dependence, such as nicotine, heroin and alcoholare often abused, and the pattern of dependence is difficult to break.Drugs that produce dependence act on the CNS and generally reduceanxiety and tension; produce elation, euphoria, or other pleasurablemood changes; provide the user feelings of increased mental and physicalability; or alter sensory perception in some pleasurable manner. Amongthe drugs that are commonly abused are ethyl alcohol, opioids,anxiolytics, hypnotics, cannabis (marijuana), cocaine, amphetamines, andhallucinogens. The current treatment for drug-addicted people ofteninvolves a combination of behavioral therapies and medications.Medications, such as methadone or LAAM (levo-alpha-acetyl-methadol), areeffective in suppressing the withdrawal symptoms and drug cravingassociated with narcotic addiction, thus reducing illicit drug use andimproving the chances of the individual remaining in treatment. Theprimary medically assisted withdrawal method for narcotic addiction isto switch the patient to a comparable drug that produces milderwithdrawal symptoms, and then gradually taper off the substitutemedication. The medication used most often is methadone, taken orallyonce a day. Patients are started on the lowest dose that prevents themore severe signs of withdrawal and then the dose is gradually reduced.Substitutes can be used also for withdrawal from sedatives. Patients canbe switched to long-acting sedatives, such as diazepam or phenobarbital,which are then gradually reduced.

[0526] Gilles de la Tourette's Syndrome is an inherited neurologicaldisorder. The disorder is characterized by uncontrollable vocal soundscalled tics and involuntary movements. The symptoms generally manifestin an individual before the person is 18 years of age. The movementdisorder may begin with simple tics that progress to multiple complextics, including respiratory and vocal ones. Vocal tics may begin asgrunting or barking noises and evolve into compulsive utterances.Coprolalia (involuntary scatologic utterances) occurs in 50% ofpatients. Severe tics and coprolalia may be physically and sociallydisabling. Tics tend to be more complex than myoclonus, but less flowingthan choreic movements, from which they must be differentiated. Thepatient may voluntarily suppress them for seconds or minutes.

[0527] Currently simple tics are often treated with benzodiazepines. Forsimple and complex tics, Clonidine may be used. Long-term use ofClonidine does not cause tardive dyskinesia; its limiting adverse effectis hypotension. In more severe cases, antipsychotics, such asHaloperidol may be required, but side effects of dysphoria,parkinsonism, akathisia, and tardive dyskinesia may limit use of suchantipsychotics. There is a need for safe and effective methods fortreating this syndrome.

[0528] Age-related macular degeneration (AMD) is a common eye disease ofthe macula which is a tiny area in the retina that helps produce sharp,central vision required for “straight ahead” activities that includereading and driving. Persons with AMD lose their clear, central vision.AMD takes two forms: wet and dry. In dry AMD, there is a slow breakdownof light-sensing cells in the macula. There currently is no cure for dryAMD. In wet AMD, new, fragile blood vessels growing beneath the maculaas dry AMD worsens and these vessels often leak blood and fluid to causerapid damage to the macula quickly leading to the loss of centralvision. Laser surgery can treat some cases of wet AMD. Therefore, thereis a need of a pharmaceutical agent to address AMD.

[0529] Glaucoma is within a group of diseases occurs from an increase inintraocular pressure causing pathological changes in the optical diskand negatively affects the field of vision. Medicaments to treatglaucoma either decrease the amount of fluid entering the eye orincrease drainage of fluids from the eye in order to decreaseintraocular pressure. However, current drugs have drawbacks such as notworking over time or causing side effects so the eye-care professionalhas to either prescribe other drugs or modify the prescription of thedrug being used. There is a need for safe and effective methods fortreating problems manifesting into glaucoma.

[0530] Ischemic periods in glaucoma cause release of excitotoxic aminoacids and stimulate inducible form of nitric oxide synthase (iNOS)leading to neurodegeneration. Alpha 7 nicotinic agonists may stimulatethe release of inhibitory amino acids such as GABA which will dampenhyperexcitablity. Alpha 7 nicotinic agonists are also directlyneuroprotective on neuronal cell bodies. Thus alpha 7 nicotinic agonistshave the potential to be neuroprotective in glaucoma.

[0531] Persons afflicted with pain often have what is referred to as the“terrible triad” of suffering from the pain, resulting in sleeplessnessand sadness, all of which are hard on the afflicted individual and thatindividual's family. Pain can manifest itself in various forms,including, but not limited to, headaches of all severity, back pain,neurogenic, and pain from other ailments such as arthritis and cancerfrom its existence or from therapy to eradicate it. Pain can be eitherchronic (persistent pain for months or years) or acute (short-lived,immediate pain to inform the person of possible injury and need oftreatment). Persons suffering from pain respond differently toindividual therapies with varying degrees of success. There is a needfor safe and effective methods for treating pain.

[0532] Finally, the compounds of the present invention may be used incombination therapy with typical and atypical anti-psychotic drugs (alsocalled an anti-psychotic agent). All compounds within the presentinvention are useful for and may also be used in combination with eachother to prepare pharmaceutical compositions. Such combination therapylowers the effective dose of the anti-psychotic drug and thereby reducesthe side effects of the anti-psychotic drugs. Some typicalanti-psychotic drugs that may be used in the practice of the inventioninclude Haldol. Some atypical anti-psychotic drugs include Ziprasidone,Olanzapine, Resperidone, and Quetiapine.

[0533] Compounds of Formula I can be prepared as shown in Scheme 1. Thekey step in the preparation of this class of compounds is the couplingof an amino-azabicyclic moiety with the requisite acid chloride (Lv=Cl),mixed anhydride (e.g., Lv=diphenyl phosphoryl,bis(2-oxo-3-oxazolidinyl)phosphinyl, or acyloxy of the general formulaof O—C(O)—R_(Lv), where R_(Lv) includes phenyl or t-butyl), orcarboxylic acid (Lv=OH) in the presence of an activating agent. Suitableactivating regents are well known in the art, for examples see Kiso, Y.,Yajima, H. “Peptides” pp. 39-91, San Diego, Calif., Academic Press,(1995), and include, but are not limited to, agents such ascarbodiimides, phosphonium and uronium salts (such as HATU).

Scheme 1 Lv-C(O—W+Azabicyclo-NH₂→Azabicyclo-N(H)—C(O)—W

[0534] Generally, the acid is activated using HATU or is converted tothe acyl azide by using DPPA or is converted into a mixed anhydride bytreatment with bis (2-oxo-3-oxazolidinyl) phosphinic chloride in thepresence of TEA with CH₂Cl₂ or CHCl₃ as the solvent; the resultinganhydride solution is directly reacted with the appropriate Azabicyclomoiety added neat or using DMF or aqueous DMF as solvent. In some cases,the ester (Lv being OMe or OEt) may be reacted directly with the aminein refluxing methanol or ethanol to give the compounds of Formula I.

[0535] The appropriate amine is treated with TEA if the amine is in theform of an acid salt and added to a solution of the appropriateanhydride or azide to give the desired final compounds. In some cases,the ester (Lv being OMe or OEt) may be reacted directly with the aminein refluxing methanol or ethanol to give the compounds of Formula I.

[0536] One of ordinary skill in the art will recognize that the methodsdescribed for the reaction of the unsubstituted 3-aminoquinuclidine (R₂is H) are equally applicable to substituted compounds (R₂ is other thanH). Certain 6-substituted-[2.2.2]-3-amines (Azabicyclo I) are known inthe art. The preparation of compounds where R₂ is at C-6 of thequinuclidine and is other than H is described in Acta Pol. Pharm. 1981,179. Certain 2-substituted-[2.2.2]-3-amines (Azabicyclo I) are known inthe art. The preparation of compounds where R₂ is at C-2 of thequinuclidine and is other than H is described in J. Med. Chem. 1975, 18,587.

[0537] Alternatively, there are several methods to obtain the amineprecursor for Azabicyclo I where R₂ is other than H. Although the schemedepicted below is for compounds where R₂ is at the C-6 position of thequinuclidine, one of ordinary skill in the art would be able to obtainthe quinuclidine with substitution at C-2 also. Thesubstituted-[2.2.2]-3-amine can be prepared by reduction of an oxime oran imine of the corresponding substituted-3-quinuclidinone by methodsknown to one of ordinary skill in the art (see J. Labelled Compds.Radiopharm. 1995, 53; J. Med. Chem. 1998, 988; Synth. Commun. 1992,1895; Synth. Commun. 1996, 2009). Alternatively, thesubstituted-[2.2.2]-3-amine can be prepared from asubstituted-3-hydroxyquinuclidine by Mitsunobu reaction followed bydeprotection as described in Synth. Commun. 1995, 1895. Alternatively,the substituted-[2.2.2]-3-amine can be prepared by conversion of asubstituted-3-hydroxyquinuclidine into the corresponding mesylate ortosylate, followed by displacement with sodium azide and reduction asdescribed in J. Med. Chem. 1975, 587.

[0538] The 2-substituted-3-quinuclidinones, where R₂ is substitutedalkyl or cycloalkyl, can be prepared by known procedures (see Tet. Lett.1972, 1015; J. Am. Chem. Soc. 1994, 1278; J. Am. Chem. Soc. 1989, 4548;Tetrahedron, 2000, 1139). The 2-substituted-3-quinuclidinones, where R₂is aryl, can be prepared by palladium catalyzed arylation as describedin J. Am. Chem. Soc. 1999, 1473 and J. Am. Chem. Soc. 2000, 1360. The6-substituted-3-quinuclidinones can be prepared by known procedures (seeJ. Gen. Chem. Russia 1963, 3791, J. Chem. Soc. Perkin Trans. I 1991,409, J. Org. Chem. 2000, 3982).

[0539] One of ordinary skill in the art will recognize that the methodsdescribed for the reaction of the unsubstituted3-amino-1-azabicyclo[2.2.1]heptane (R₂═H) are equally applicable tosubstituted compounds (R₂≠H). For where Azabicyclo II has substitutionat C-2, compounds can be prepared from appropriately substituted nitroalcohols using procedures described in Tetrahedron 1997, 53, p. 11121 asshown below. Methods to synthesize nitro alcohols are well known in theart (see J. Am. Chem. Soc. 1947, 69, p 2608). The scheme below is amodification of the synthesis of exo-3-amino-1-azabicyclo[2.2.1]heptaneas the bis(hydro para-toluenesulfonate) salt, described in detailherein, to show how to obtain these amine precursors. The desired saltcan be made using standard procedures.

[0540] For Azabicyclo II where R₂ is other than H at the C-6 position,compounds can also be prepared by modification of intermediatesdescribed in the synthesis of exo-3-amino-1-azabicyclo[2.2.1]heptane asthe bis(hydro para-toluenesulfonate) salt, described in detail herein.For example, Int 6 can be oxidized to the aldehyde and treated with anorganometallic reagent to provide Int 20 using procedures described inTetrahedron 1999, 55, p 13899. Int 20 can be converted into the amineusing methods described for the synthesis ofexo-3-amino-1-azabicyclo[2.2.1]heptane as the bis(hydropara-toluenesulfonate) salt. Once the amine is obtained, the desiredsalt can be made using standard procedures.

[0541] The schemes used are for makingexo-3-amino-1-azabicyclo[2.2.1]heptane. However, the modificationsdiscussed are applicable to make the endo isomer also.

[0542] One of ordinary skill in the art will also recognize that themethods described for the reaction of the unsubstituted1-azabicyclo[3.2.1]octan-3-amine or 1-azabicyclo[3.2.2]nonan-3-amine(R₂═H) are equally applicable to substituted compounds (R₂≠H). The R₂substituent may be introduced as known to one skilled in the art throughstandard alkylation chemistry. Exposure of1-azabicyclo[3.2.1]octan-3-one or 1-azabicyclo[3.2.2]nonan-3-one to ahindered base such as LDA (lithium diisopropylamide) in a solvent suchas THF or ether between 0° C. to −78° C. followed by the addition of analkylating agent (R₂Lv, where Lv=Cl, Br, I, OTs, etc.) will, after beingallowed to warm to about 0° C. to rt followed by an aqueous workup,provide the desired compound as a mixture of isomers. Chromatographicresolution (flash, HPLC, or chiral HPLC) will provided the desiredpurified alkylated ketones. From there, formation of the oxime andsubsequent reduction will provide the desired stereoisomers.

[0543] N-(2-azabicyclo[2.2.1]hept)-5-amine and 6-amine

[0544] where Lv can be —CH₂Ph, —CH(Me)Ph, —OH, —OMe, or —OCH₂Ph.

[0545] The respective amine precursors for Azabicyclo V and AzabicycloVI can be prepared by reduction of an oxime or an imine of thecorresponding N-2-azabicyclo[2.2.1]-heptanone by methods known to oneskilled in the art (see J. Labelled Compds. Radiopharm., 53-60 (1995),J. Med. Chem. 988-995, (1998), Synth. Commun. 1895-1911 (1992), Synth.Commun. 2009-2015 (1996)). The oximes can be prepared by treatment ofthe N-2-azabicyclo[2.2.1]heptanones with hydroxylamine hydrochloride inthe presence of a base. The imines can be prepared by treatment of theN-2-azabicyclo[2.2.1]-heptanones with a primary amine under dehydratingconditions. The N-2-azabicyclo[2.2.1]heptanones can be prepared by knownprocedures (see Tett. Lett. 1419-1422 (1999), J. Med. Chem. 2184-2191(1992), J. Med. Chem. 706-720 (2000), J. Org. Chem., 4602-4616 (1995)).

[0546] It will be apparent to those skilled in the art that therequisite carboxylic acids can be obtained through synthesis vialiterature procedures or through the slight modification thereof.

Amines Preparation ofN-(2S,3R)-2-methyl-1-azabicyclo[2.2.2]octan-3-amine dihydrochloride(2S-methyl-2.2.2-Amine)

[0547] A mixture of 2-methylene-3-quinuclidinone dihydrate hydrochloride(27.18 g, 0.1296 mol, 1 eq) and K₂CO₃ (86.0 g, 0.6213 mol, 4.8 eq) isdissolved in 130 mL water and 250 mL CH₂Cl₂ and stirred vigorously.After 3 days, the layers are separated and the aqueous layer isextracted with CH₂Cl₂. The combined organic layers are dried (MgSO₄),filtered and concentrated to give 17.8 g (100%) of2-methylenequinuclidin-3-one as a yellow oil. MS (ESI) for C₈H₁₁NO m/z138.1 (M⁺).

[0548] 2-Methylenequinuclidin-3-one (17.8 g, 0.1296 mol, 1 eq) isdissolved in 40 mL MeOH in a Parr hydrogenation bottle. A THF slurry of10% Pd/C (0.57 g) is added. The mixture is hydrogenated for 45 min at 45psi, recharging as needed. The mixture is filtered through a pad ofCelite. The Celite is washed with excess MeOH. The solution isconcentrated to give a solid and a yellow oil. The mixture is taken upin ether, filtered and concentrated to provide 16.2 g (90%) of2-methylquinuclidin-3-one. MS (ESI) for C₈H₁₃NO m/z 140.2 (M⁺).

[0549] 2-Methylquinuclidin-3-one (39.59 g, 0.2844 mol, 1 eq) andhydroxylamine hydrochloride (20.0 g, 0.2878 mol, 1.01 eq) are dissolvedin 170 mL absolute EtOH. The mixture is heated under reflux until aclear solution develops (about 20 min), after which is immediatelyfollowed by formation of a white precipitate. The reaction is cooled andallowed to stand overnight. The mixture is cooled in an ice bath, thesolids are filtered and dried (house vacuum) to provide 46.4 g of(3E/Z)-2-methyl-1-azabicyclo[2.2.2]octan-3-one oxime hydrochloride. Asecond crop of 2.4 g is also obtained. Overall yield is 48.8 g (90%).The 2-methyl-1-azabicyclo[2.2.2]octan-3-one oxime hydrochloride is a 4:1mixture of oxime isomers. MS (ESI) for C₈H₁₄N₂O m/z 154.8 (M⁺). Partial¹H NMR (400 MHz, DMSO) δ 4.39 (0.2H), 4.29 (0.8 H), 1.57 (0.6 H), 1.47(2.4 H).

[0550] A solution of sodium n-propoxide (prepared from 5.5 g sodium(0.24 mol) and 100 mL n-propanol) is added dropwise to a suspension of(3E/Z)-2-methyl-1-azabicyclo[2.2.2]octan-3-one oxime hydrochloride (45.8g, 0.24 mol, 1 eq) in 150 mL n-propanol. After complete addition, 250 mLof n-propanol is added, and the mixture is heated under reflux. Sodium(55.2 g, 2.40 mol, 10 eq) is added in portions to the refluxing mixture.The mixture is heated under reflux overnight. After about 14 h, themixture is cooled, water is added and the layers are separated. Then-propanol layer is washed with brine and dried (MgSO₄). The combinedaqueous layers are extracted with CHCl₃ and dried (MgSO₄). The combined,dried organic layers are treated with about 70 mL concentrated HCl. Thesolvent is removed in vacuo. Absolute EtOH is added, and the solvent isremoved. The sequence is repeated 2-3 times with fresh EtOH until awhite solid formed. Absolute EtOH is added, the solids are filtered anddried (vacuum oven, about 60° C.) to provide 36.5 g of trans3-amino-2-methylquinuclidine dihydrochloride. MS (ESI) for C₈H₁₆N₂ m/z141.3 (M⁺). Additional material is obtained from the mother liquor: 7.8g (2^(nd) crop) and 1.5 g (3^(rd) crop); this material is a mixture ofboth trans and cis isomers.

[0551] 4-Chlorobenzoic acid (26.3 g, 0.1681 mol, 1.1 eq) and TEA (106mL, 0.764 mol, Seq.) are dissolved in 300 mL THF. Diphenylphosphorylchloride (32.0 mL, 0.1681 mol, 1.1 eq) is added dropwise. After 1 h,trans 2-methylquinuclidin-3-amine dihydrochloride (32.6 g, 0.1528 mol, 1eq) is added. The mixture is allowed to stir at RT overnight. 1N NaOH(about 100 mL) is added, and the pH is adjusted to pH 11 with 50% NaOHand about 50 g K₂CO₃. The layers are separated. The aqueous layer isextracted with CHCl₃. The combined organic layers are dried (MgSO₄),filtered and concentrated. The residue is taken up in heptane andconcentrated to give 35.1 g (82%) of4-chloro-N-(2-methyl-1-azabicyclo[2.2.2]oct-3-yl)phenyl-2-carboxamide asa light yellow solid. The enantiomers are separated on a 5×50 cmChiralcel OD column at 30° C., eluting with 15% IPA/heptane +0.1% DEA at90 mL/min to provide 17.4 g of the eutomer at about 97% ee. The p-TsOHsalt is prepared and recrystallized from EtOH/EtOAc. [α]²⁵ _(D)=+3° (c0.96, methanol). HRMS (FAB) calcd for C₁₅H₁₉ClN₂O+H 279.1264, found279.1272.

[0552] A solution of4-chloro-N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]benzamide (17.2g, 61.7 mmol) in absolute EtOH (70 mL) and concentrated HCl (70 mL) isheated under reflux for about 64 h. The reaction is monitored fordisappearance of starting amide by reverse phase HPLC (ZORBAX EclipseXDB—C8, 4.6 mm×15 cm, 80:12:8 H₂O/CH₃CN/IPA). The solvent is removed invacuo. The residue is dissolved/suspended in EtOH and the solvent isremoved (twice). The solid is suspended in boiling EtOH, filtered anddried (vacuum oven, about 60° C.) to provide 8.8 g (67%) ofN-(2S,3R)-2-methyl-1-azabicyclo[2.2.2]octan-3-amine dihydrochloride as awhite solid. MS (EI) m/z 141.2 (M⁺).

Step A. Preparation of 2-(benzoyloxy)-1-nitroethane (Int 1)

[0553] Benzoyl chloride (14.9 mL, 128 mmol) is added to a stirredsolution of nitroethanol (9.2 mL, 128 mmol) in dry benzene (120 mL). Thesolution is refluxed for 24 hr and then concentrated in vacuo. The crudeproduct is purified by flash chromatography on silica gel. Elution withhexanes-EtOAc (80:20) affords Int I as a white solid (68% yield): ¹H NMR(300 MHz, CDCl₃) δ 8.0, 7.6, 7.4, 4.9, 4.8.

Step B. Preparation of ethyl E-4-(benzylamino)-2-butenoate (Int 2)

[0554] Ethyl E-4-bromo-2-butenoate (10 mL, 56 mmol, tech grade) is addedto a stirred solution of benzylamine (16 mL, 146 mmol) in CH₂Cl₂ (200mL) at rt. The reaction mixture stirs for 15 min, and is diluted withether (1 L). The mixture is washed with saturated aqueous NaHCO₃solution (3×) and water, dried over Na₂SO₄, filtered and concentrated invacuo. The residue is purified by flash chromatography on silica gel.Elution with hexanes-EtOAc (70:30) affords Int 2 as a clear oil (62%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.4-7.2, 7.0, 6.0, 4.2, 3.8, 3.4,2.1-1.8, 1.3.

Step C. Preparation oftrans-4-nitro-1-(phenylmethyl)-3-pyrrolidineacetic acid ethyl ester (Int3)

[0555] A solution of Int 1 (6.81 g, 34.9 mmol) and Int 2 (7.65 g, 34.9mmol) in EtOH (70 mL) stirs at rt for 15 h and is then concentrated invacuo. The residue is diluted with ether (100 mL) and saturated aqueousNaHCO₃ solution (100 mL). The organic layer is separated and dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product ispurified by flash chromatography on silica gel. Elution withhexanes-EtOAc (85:15) affords Int 3 as a clear oil (76% yield): ¹H NMR(300 MHz, CDCl₃) δ 7.4-7.3, 4.8-4.7, 4.1, 3.8-3.6, 3.3-3.0, 2.7-2.6,2.4-2.3, 1.2.

Step D. Preparation oftrans-4-amino-1-(phenylmethyl)-3-pyrrolidineacetic acid ethyl ester (Int4)

[0556] A mixture of Int 3 (3.28 g, 11.2 mmol) and RaNi (1.5 g) in EtOH(100 mL) is placed in a Parr bottle and hydrogenated for 4 h under anatmosphere of hydrogen (46 psi) at rt. The mixture is filtered through apad of Celite, and the solvent is removed in vacuo to afford Int 4 as aclear oil (100% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.3-7.2, 4.1, 3.6,3.2, 3.0-2.9, 2.8, 2.8-2.6, 2.6-2.4, 2.30-2.2, 1.2.

Step E. Preparation oftrans-4-(1,1-dimethylethoxycarbonylamido)-1-(phenylmethyl)-3-pyrrolidineaceticacid ethyl ester (Int 5)

[0557] Di-tert-butyldicarbonate (3.67 g, 16.8 mmol) is added to astirred solution of Int 4 (2.94 g, 11.2 mmol) in CH₂Cl₂ (30 mL) cooledin an ice bath. The reaction is allowed to warm to rt and stirredovernight. The mixture is concentrated in vacuo. The crude product ispurified by flash chromatography on silica gel. Elution withhexanes-EtOAc (80:20) affords Int 5 as a white solid (77% yield): ¹H NMR(300 MHz, CDCl₃) δ 7.4-7.2, 5.1-4.9, 4.1, 4.0-3.8, 3.6, 3.2-3.0,2.8-2.6, 2.5-2.4, 2.3-2.1, 1.4, 1.3.

Step F. Preparation of trans(tert-butoxycarbonylamino)-4-(2-hydroxyethyl)-1-(N-phenylmethyl)pyrrolidine (Int 6)

[0558] LiAlH₄ powder (627 mg, 16.5 mmol) is added in small portions to astirred solution of Int 5 (3.0 g, 8.3 mmol) in anhydrous THF (125 mL) ina −5° C. bath. The mixture is stirred for 20 min in a −5° C. bath, thenquenched by the sequential addition of water (0.6 mL), 15% (w/v) aqueousNaOH (0.6 mL) and water (1.8 mL). Excess anhydrous K₂CO₃ is added, andthe mixture is stirred for 1 h, then filtered. The filtrate isconcentrated in vacuo. The residue is purified by flash chromatographyon silica gel. Elution with EtOAc affords Int 6 as a white solid (94%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.4-7.3, 5.3-5.2, 4.1-4.0, 3.9-3.7,3.3-3.2, 2.8-2.7, 2.3-2.1, 1.7 1.5.

[0559] Int 6 is a racemic mixture that can be resolved viachromatography using a Diacel chiral pack AD column. From the twoenantiomers thus obtained, the (+)-enantiomer, [α]²⁵ _(D)+35 (c 1.0,MeOH), gives rise to the corresponding enantiomerically pure exo-4-Sfinal compounds, whereas the (−)-enantiomer, [α]²⁵ _(D)34 (c 0.98,MeOH), gives rise to enantiomerically pure exo-4-R final compounds. Themethods described herein use the (+)-enantiomer of Int 6 to obtain theenantiomerically pure exo-4-S final compounds. However, the methods usedare equally applicable to the (−)-enantiomer of Int 6, makingnon-critical changes to the methods provided herein to obtain theenantiomerically pure exo-4-R final compounds.

Step G. Preparation of exo3-(tert-butoxycarbonylamino)-1-azabicyclo[2.2.1]heptane (Int 7)

[0560] TEA (8.0 g, 78.9 mml) is added to a stirred solution of Int 6(2.5 g, 7.8 mmol) in CH₂Cl₂ (50 mL), and the reaction is cooled in anice-water bath. CH₃SO₂Cl (5.5 g, 47.8 mmol) is then added dropwise, andthe mixture is stirred for 10 min in an ice-water bath. The resultingyellow mixture is diluted with saturated aqueous NaHCO₃ solution,extracted with CH₂Cl₂ several times until no product remains in theaqueous layer by TLC. The organic layers are combined, washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. The residue isdissolved in EtOH (85 mL) and is heated to reflux for 16 h. The reactionmixture is allowed to cool to rt, transferred to a Parr bottle andtreated with 10% Pd/C catalyst (1.25 g). The bottle is placed under anatmosphere of hydrogen (53 psi) for 16 h. The mixture is filteredthrough Celite, and fresh catalyst (10% Pd/C, 1.25 g) is added.Hydrogenolysis continues overnight. The process is repeated three moretimes until the hydrogenolysis is complete. The final mixture isfiltered through Celite and concentrated in vacuo. The residue ispurified by flash chromatography on silica gel. Elution withCHCl₃—MeOH—NH₄OH (90:9.5:0.5) affords Int 7 as a white solid (46%yield): ¹H NMR (300 MHz, CDCl₃) δ 5.6-5.5, 3.8-3.7, 3.3-3.2, 2.8-2.7,2.0-1.8, 1.7-1.5, 1.5.

Step H. Preparation of exo-3-amino-1-azabicyclo[2.2.1]heptanebis(hydro-para-toluenesulfonate)

[0561] Para-toluenesulfonic acid monohydrate (1.46 g, 7.68 mmol) isadded to a stirred solution of Int 7 (770 mg, 3.63 mmol) in EtOH (50mL). The reaction mixture is heated to reflux for 10 h, followed bycooling to rt. The precipitate is collected by vacuum filtration andwashed with cold EtOH to give exo-[2.2.1]-Amine as a white solid (84%yield): ¹H NMR (400 MHz, CD₃OD) δ 7.7, 7.3, 3.9-3.7, 3.7-3.3, 3.2, 2.4,2.3-2.2, 1.9-1.8.

[0562] Synthesis of endo-3-amino-1-azabicyclo[2.2.1]heptane as thebis(hydro para-toluenesulfonate) salt (endo-[2.2.1]-Amine):

Step I. Preparation of ethyl5-hydroxy-6-oxo-1,2,3,6-tetrahydropyridine-4-carboxylate (Int 10)

[0563] Absolute EtOH (92.0 mL, 1.58 mol) is added to a mechanicallystirred suspension of potassium ethoxide (33.2 g, 395 mmol) in drytoluene (0.470 L). When the mixture is homogeneous, 2-pyrrolidinone(33.6 g, 395 mmol) is added, and then a solution of diethyl oxalate(53.1 mL, 390 mmol) in toluene (98 mL) is added via an addition funnel.After complete addition, toluene (118 mL) and EtOH (78 mL) are addedsequentially. The mixture is heated to reflux for 18 h. The mixture iscooled to rt and aqueous HCl (150 mL of a 6.0 M solution) is added. Themixture is mechanically stirred for 15 min. The aqueous layer isextracted with CH₂Cl₂, and the combined organic layers are dried(MgSO₄), filtered and concentrated in vacuo to a yellow residue. Theresidue is recrystallized from EtOAc to afford Int 10 as a yellow solid(38% yield): ¹H NMR (300 MHz, CDCl₃) δ 11.4, 7.4, 4.3, 3.4, 2.6, 1.3.

Step J. Preparation of ethyl cis-3-hydroxy-2-oxopiperidine-4-carboxylate(Int 11)

[0564] A mixture of Int 10 (15 g, 81 mmol) and 5% rhodium on carbon (2.0g) in glacial acetic acid is placed under an atmosphere of hydrogen (52psi). The mixture is shaken for 72 h. The mixture is filtered throughCelite, and the filtrate is concentrated in vacuo to afford Int 11 as awhite solid (98% yield): ¹H NMR (300 MHz, CDCl₃) δ 6.3, 4.2, 4.0-3.8,3.4, 3.3-3.2, 2.2, 1.3.

Step K. Preparation of cis-4-(hydroxymethyl)piperidin-3-ol (Int 12)

[0565] Int 11 (3.7 g, 19.9 mmol) as a solid is added in small portionsto a stirred solution of LiAlH₄ in THF (80 mL of a 1.0 M solution) in anice-water bath. The mixture is warmed to rt, and then the reaction isheated to reflux for 48 h. The mixture is cooled in an ice-water bathbefore water (3.0 mL, 170 mmol) is added dropwise, followed by thesequential addition of NaOH (3.0 mL of a 15% (w/v) solution) and water(9.0 mL, 500 mmol). Excess K₂CO₃ is added, and the mixture is stirredvigorously for 15 min. The mixture is filtered, and the filtrate isconcentrated in vacuo to afford Int 12 as a yellow powder (70% yield):¹H NMR (300 MHz, DMSO-d₆) δ 4.3, 4.1, 3.7, 3.5-3.2, 2.9-2.7, 2.5-2.3,1.5, 1.3.

Step L. Preparation of benzylcis-3-hydroxy-4-(hydroxymethyl)piperidine-1-carboxylate (Int 13)

[0566] N-(benzyloxy carbonyloxy)succinimide (3.04 g, 12.2 mmol) is addedto a stirred solution of Int 12 (1.6 g, 12.2 mmol) in saturated aqueousNaHCO₃ (15 mL) at rt. The mixture is stirred at rt for 18 h. The organicand aqueous layers are separated. The aqueous layer is extracted withether (3×). The combined organic layers are dried over anhydrous K₂CO₃,filtered and concentrated in vacuo to afford Int 13 as a yellow oil (99%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.4-7.3, 5.2, 4.3, 4.1, 3.8-3.7,3.0-2.8, 2.1, 1.9-1.7, 1.4.

Step M. Preparation of benzyl cis-3-hydroxy-4-[(4-methylphenyl)sulfonyloxymethyl]piperidine-1-carboxylate (Int 14)

[0567] Para-toluenesulfonyl chloride (1.0 g, 5.3 mmol) is added to astirred solution of Int 13 (3.6 g, 5.3 mmol) in pyridine (10 mL) in a−15° C. bath. The mixture is stirred for 4 h, followed by addition ofHCl (4.5 mL of a 6.0 M solution). CH₂Cl₂ (5 mL) is added. The organicand aqueous layers are separated. The aqueous layer is extracted withCH₂Cl₂. The combined organic layers are washed with brine, dried(MgSO₄), filtered and concentrated in vacuo to afford Int 14 as acolorless oil (78% yield): ¹H NMR (300 MHz, CDCl₃) δ 7.8, 7.4-7.2, 5.1,4.3-4.2, 4.1, 3.9-3.8, 2.9-2.7, 2.4, 1.9, 1.6-1.3.

Step N. Preparation of exo-1-azabicyclo[2.2.1]heptan-3-ol (Int 15)

[0568] A mixture of Int 14 (3.6 g, 8.6 mmol) and 10% Pd/C catalyst (500mg) in EtOH (50 mL) is placed under an atmosphere of hydrogen. Themixture is shaken for 16 h. The mixture is filtered through Celite.Solid NaHCO₃ (1.1 g, 13 mmol) is added to the filtrate, and the mixtureis heated in an oil bath at 50° C. for 5 h. The solvent is removed invacuo. The residue is dissolved in saturated aqueous K₂CO₃ solution.Continuous extraction of the aqueous layer using a liquid-liquidextraction apparatus (18 h), followed by drying the organic layer overanhydrous K₂CO₃ and removal of the solvent in vacuo affords Int 15 as awhite solid (91% yield): ¹H NMR (300 MHz, CDCl₃) δ 3.8, 3.0-2.8,2.6-2.5, 2.4-2.3, 1.7, 1.1.

Step O. Preparation of endo-3-azido-1-azabicyclo[2.2.1]heptane (Int 16)

[0569] To a mixture of Int 15 (1.0 g, 8.9 mmol) and triphenyl phosphine(3.0 g, 11.5 mmol) in toluene-THF (50 mL, 3:2) in an ice-water bath areadded sequentially a solution of hydrazoic acid in toluene (15 mL of ca.2 M solution) and a solution of diethyl azadicarboxylate (1.8 mL, 11.5mmol) in toluene (20 mL). The mixture is allowed to warm to rt and stirfor 18 h. The mixture is extracted with aqueous 1.0M HCl solution. Theaqueous layer is extracted with EtOAc, and the combined organic layersare discarded. The pH of the aqueous layer is adjusted to 9 with 50%aqueous NaOH solution. The aqueous layer is extracted with CH₂Cl₂ (3×),and the combined organic layers are washed with brine, dried overNa₂SO₄, filtered and concentrated in vacuo. The crude product ispurified by flash chromatography on silica gel. Elution withCHCl₃—MeOH—NH₄OH (92:7:1) affords Int 16 as a colorless oil (41 %yield): ¹H NMR (300 MHz, CDCl₃) δ 4.1, 3.2, 2.8, 2.7-2.5, 2.2, 1.9, 1.5.

Step P. Preparation of endo-3-amino-1-azabicyclo[2.2.1]heptanebis(hydro-para-toluenesulfonate)

[0570] A mixture of Int 16 (250 mg, 1.8 mmol) and 10% Pd/C catalyst (12mg) in EtOH (10 mL) is placed under an atmosphere of hydrogen (15 psi).The mixture is stirred for 1 h at rt. The mixture is filtered throughCelite, and the filtrate is concentrated in vacuo. The residue isdissolved in EtOH (10 mL) and para-toluenesulfonic acid monohydrate (690mg, 3.7 mmol) is added. The mixture is stirred for 30 min, and theprecipitate is filtered. The precipitate is washed sequentially withcold EtOH and ether. The precipitate is dried in vacuo to affordendo-[2.2.1]-Amine as a white solid (85% yield): ¹H NMR (300 MHz, CD₃OD)δ 7.7, 7.3, 4.2, 3.9, 3.6-3.4, 3.3-3.2, 2.4, 2.3, 2.1.

Preparation of 1-azabicyclo[3.2.1]octan-3-amine Preparation of the3R,5R-[3.2.1]-Amine

[0571]

(3S)-1-[(S)-1-Phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid

[0572]

[0573] According to the literature procedure (Nielsen et al. J. Med.Chem 1990, 70-77), a mixture of itaconic acid (123.17 g, 946.7 mmol) and(S)-(−)-α-methyl benzylamine (122.0 mL, 946.4 mmol) were heated (neat)in a 160° C. oil bath for 4 h. Upon cooling, MeOH (˜200 mL) was addedand the resulting solid collected by filtration. The solid was treatedwith EtOH (˜700 mL) and warmed using a steam bath until ˜450 mL solventremained. After cooling to rt, the solid was collected and dried toafford 83.2 g as a white crystalline solid: [α]²⁵ _(D)=−80 (c 0.97,DMSO). MS (EI) m/z 233 (M⁺), 233, 218, 160, 105, 104, 103, 91, 79, 78,77.

[0574] The lack of a resonance 3.59 indicates a single diastereomer. Theother diastereomer can be retrieved from the initial MeOH triturant.Attempts to crystallize this material generally led to small quantitiesof (3RS)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid.

(3S)-1-[(S)-1-Phenethyl]-3-(hydroxymethyl)pyrrolidine

[0575]

[0576] A suspension(3S)-1-[(S)-1-phenethyl]-5-oxo-3-pyrrolidine-carboxylic acid (82.30 g,352.8 mmol) in Et₂O (200 mL) was added in small portions to a slurry ofLiAlH₄ (17.41 g, 458.6 mmol) in Et₂O (700 mL). The mixture began toreflux during the addition. The addition funnel containing thesuspension was rinsed with Et₂O (2×50 mL), and the mixture was heated ina 50° C. oil bath for an additional 2 h and first allowed to cool to rtand then further cooled using an ice bath. The mixture was carefullytreated with H₂O (62 mL). The resulting precipitate was filtered, rinsedwith Et₂O, and discarded. The filtrate was concentrated to a yellow oil.When EtOAc was added to the oil, a solid began to form. Hexane was thenadded and removed by filtration and dried to afford 43.3 g as a whitesolid. [α]²⁵ _(D)=−71 (c 0.94, CHCl₃). MS (EI) m/z 205 (M⁺), 191, 190,128, 105, 91, 86, 84, 79, 77, 51.

(3R)-1-[(S)-1-Phenethyl]-3-(cyanomethyl)pyrrolidine

[0577]

[0578] A solution of(3S)-1-[(S)-1-phenethyl]-3-(hydroxymethyl)pyrrolidine (42.75 g, 208.23mmol) in chloroform (350 mL) was heated to reflux under N₂. The solutionwas treated with a solution of thionyl chloride (41.8 mL, 573 mmol) inchloroform (40 mL) dropwise over 45 min. The mixture stirred for anadditional 30 min, was cooled and concentrated. The residue was dilutedwith H₂O (−200 mL), 1 N NaOH was added until a pH ˜8 (pH paper). A smallportion (˜50 mL) of sat. NaHCO₃ was added and the basic mixture wasextracted with EtOAc (3×400 mL), washed with brine, dried (MgSO₄),filtered and concentrated to give 46.51 g of a red-orange oil for(3S)-1-[(S)-1-phenethyl]-3-(chloromethyl)pyrrolidine: R_(f): 0.50(EtOAc-hexane 1:1); MS (ESI+) m/z 224.2 (MH⁺). The chloride (46.35 g,208.0 mmol) was transferred to a flask, dimethyl sulfoxide (200 mL) wasadded, and the solution was treated with NaCN (17.84 g, 363.9 mmol). Themixture was heated under N₂ in a 100° C. oil bath overnight and wascooled. The brown mixture was poured into H₂O (300 mL) and extractedwith EtOAc (1000 mL in portions). The combined organic layer was washedwith H₂O (6×˜50 mL), brine (˜100 mL), dried (MgSO₄), filtered andconcentrated to give 40.61 g as an orange-red oil: R_(f): 0.40(EtOAc-PhCH₃ 1:1). MS (ESI+) for m/z 215.2 (M+H⁺).

(3R)-Methyl 1-[(S)-1-phenylethyl]pyrrolidine-3-acetate

[0579]

[0580] Acetyl chloride (270 mL, 3.8 mol) was carefully added to a flaskcontaining chilled (0° C.) methanol (1100 mL). After the addition wascomplete, the acidic solution stirred for 45 min (0° C.) and then(3R)-1-[(S)-1-phenethyl]-3-(cyanomethyl)pyrrolidine (40.50 g, 189.0mmol) in methanol (200 mL) was added. The ice bath was removed and themixture stirred for 100 h at rt. The resulting suspension wasconcentrated. Water (˜600 mL) was added, the mixture stirred for 45 minand then the pH was adjusted (made basic) through the addition of ˜700mL sat. aq. NaHCO₃. The mixture was extracted with EtOAc (3×300 mL). Thecombined organics were washed with brine, dried (MgSO₄), filteredthrough celite and concentrated to give 36.86 g as an orange-red oil. MS(ESI+) m/z 248.2 (M+H⁺).

(5R)-1-Azabicyclo[3.2.1]octan-3-one hydrochloride

[0581]

[0582] A solution of (3R)-methyl1-[(S)-1-phenylethly]pyrrolidine-3-acetate (25.72 g, 104.0 mmol) in THF(265 mL) was cooled under N₂ in a CO₂/acetone bath. Next, ICH₂Cl (22.7mL, 312.0 mmol) was added, and the mixture stirred for 30 min. Asolution of 2.0M lithium diisopropylamide (heptane/THF/ethylbenzene, 156mL, 312 mmol) was added slowly over 30 min. The internal temperaturereached a maximum of −40° C. during this addition. After 1 h, sat. NH₄Cl(100 mL) was added and the mixture was allowed to warm to rt. Theorganic layer was separated, dried (MgSO₄), filtered and concentrated.The resulting red-brown foam was chromatographed (300 g SiO₂,CHCl₃—MeOH—NH₄OH (89:10:1) followed by CHCl₃—MeOH (3:1). The productfractions were pooled and concentrated to afford(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride(10.12 g) as a tan foam (MS (ESI+) m/z 230.1 (M+H⁺). This foam (10.1 g,38 mmol) was taken up in MeOH (500 mL), 10% Pd(C) (3.0 g) added and themixture was hydrogenated (45 psi) overnight. The mixture was filteredand re-subjected to the reduction conditions (9.1 g, 10% Pd/C, 50 psi).After 5 h, TLC indicated the consumption of the(5R)-3-oxo-1-[(1S)-1-phenylethyl]-1-azoniabicyclo[3.2.1]octane chloride.The mixture was filtered, concentrated and triturated (minimal iPrOH) togive 3.73 g of (5R)-1-azabicyclo[3.2.1]octan-3-one hydrochloride, in twocrops, as an off-white solid: [α]²⁵ _(D)=33 (c 0.97, DMSO). MS (EI) m/z125 (M⁺).

(3R,5R)-1-azabicyclo[3.2.1]octan-3-amine dihydrochloride

[0583]

[0584] To a flask containing (SR)-1-azabicyclo[3.2.1]octan-3-onehydrochloride (3.64 g, 22.6 mmol), hydroxylamine hydrochloride (2.04 g,29.4 mmol), and ethanol (130 mL) was added sodium acetate trihydrate(9.23 g, 67.8 mmol). The mixture stirred for 3 h and was filtered andconcentrated. The resulting white solid was taken up in n-propanol (100mL) and sodium (˜13.6 g, 618 mmol) was added over 20-25 portions. Thereaction spontaneously began to reflux, and the reaction was heated inan oil bath (100° C.). The addition was complete in ˜20 min and themixture had solidified after ˜40 min. The oil bath was removed andn-propanol (2×25 mL) was added dissolving the remaining sodium metal.The mixture was carefully quenched through the dropwise addition of H₂O(100 mL). Saturated aq. NaCl (20 mL) was added, and the layers wereseparated. The organic layer was dried (MgSO₄), filtered, treated withfreshly prepared MeOH/HCl, and concentrated. The resulting solid wastriturated with 30 mL EtOH, filtered and dried in vaccuo to afford 3.51g as a white solid: [α]²⁵ _(D)=−3 (c 0.94, DMSO). MS (FAB) m/z 127(MH⁺).

Preparation of endo-1-azabicyclo[3.2.1]octan-3-amine dihydrochloride(endo-[3.2.1]-Amine)

[0585]

[0586] A mixture of 1-azabicyclo[3.2.1]octan-3-one hydrochloride (2.80g, 17.3 mmol), ethanol (25 mL), and hydroxylamine hydrochloride (1.56 g,22.4 mmol) is treated with sodium acetate trihydrate (7.07 g, 51.2mmol). The mixture is stirred for 3 h and evaporated in vacuo. Theresidue is diluted with CH₂Cl₂, treated with charcoal, filtered andevaporated. The resulting oxime (3.1 mmol) is treated with acetic acid(30 mL) and hydrogenated at 50 psi over PtO₂ (50 mg) for 12 h. Themixture is then filtered and evaporated. The residue is taken up in aminimal amount of water (6 mL) and the pH is adjusted to >12 using solidNaOH. The mixture is then extracted with ethyl acetate (4×25 mL), dried(MgSO₄), filtered, treated with ethereal HCl, and evaporated to give thegive endo-[3.2.1]-Amine.

Preparation of the 3.2.2 Amines

[0587]

Preparation of tert-butyl 4-(2-oxopropylidene)piperidine-1-carboxylate(Int 101)

[0588] Sodium hydride (60% oil dispersion, 2.01 g, 50.2 mmol) is washedwith pentane (3×) and suspended in dry THF (40 mL). The solution iscooled to 0° C. before diethyl (2-oxopropyl)phosphonate (9.75 g, 50.2mmol) is added dropwise. After complete addition, the solution is warmedto rt and stirred for 30 min. tert-Butyl 4-oxo-1-piperidinecarboxylate(5.0 g, 25.1 mmol) is added in portions over 10 min, followed bystirring at rt for 2 h. A saturated aqueous solution of ammoniumchloride is added, followed by dilution with ether. The organic layer isextracted with water. The organic layer is dried over anhydrous MgSO₄,filtered and concentrated to a yellow oil. The crude product is purifiedby flash chromatography on silica gel. Elution with hexanes-ether(60:40) gave 4.5 g (75%)of Int 101 as a white solid: ¹H NMR (400 MHz,CDCl₃) δ 6.2, 3.5, 3.4, 2.9, 2.3, 2.2, 1.5.

Preparation of tert-butyl 4-(2-oxopropyl)piperidine-1-carboxylate (Int102)

[0589] A mixture of Int 101 (4.5 g, 19 mmol) and 10% palladium onactivated carbon (450 mg) in EtOH (150 mL) is placed in a Parr bottleand hydrogenated for 5 h at 50 psi. The mixture is filtered throughCelite, and the filtrate is concentrated in vacuo to afford 4.3 g (94%)of Int 102 as a clear oil: ¹H NMR (400 MHz, CDCl₃) δ 4.1, 2.8, 2.4, 2.2,2.0, 1.7, 1.5, 1.1.

Preparation of tert-butyl4-(3-bromo-2-oxopropyl)piperidine-1-carboxylate (Int 103)

[0590] To a stirred solution lithium hexamethyldisilylamide in THF (20.0 mL, 1.0 M) in a −78° C. bath is added chlorotrimethylsilane (11.0 mL,86.4 mmol) dropwise. The mixture is stirred at −78° C. for 20 min,followed by addition of Int 102 (3.21 g, 13.3 mmol) in a solution of THF(50 mL) dropwise. After complete addition, the mixture is stirred at−78° C. for 30 min. The mixture is warmed to 0° C. in an ice-water bathand phenyltrimethylammonium tribromide (5.25 g, 14.0 mmol) is added. Themixture is stirred in an ice-bath for 30 min, followed by the additionof water and ether. The aqueous layer is washed with ether, and thecombined organic layers are washed with saturated aqueous sodiumthiosulfate solution. The organic layer is dried over anhydrous MgSO₄,filtered and concentrated in vacuo to afford a yellow oil. The crudeproduct is purified by flash chromatography on silica gel. Elution withhexanes-ether (60:40) gave 2.2 g (52%) of Int 103 as a lt. yellow oil:¹H NMR (400 MHz, CDCl₃) δ 4.2-4.1, 3.9, 2.8, 2.7, 2.6, 2.1-2.0, 1.7,1.5, 1.2-1.1.2.

Preparation of 1-bromo-3-piperidin-4-ylacetone trifluoroacetate (Int104)

[0591] To a stirred solution of Int 103 (2.2 g, 6.9 mmol) in CH₂Cl₂ (30mL) in an ice-water bath is added trifluoroacetic acid (10 mL, 130mmol). The mixture is stirred at 0° C. for 30 min. The volatiles areremoved in vacuo to afford 2.0 g (87%) of Int 104 as a yellow residue:MS (ESI) for C₈H₁₅BrNO [M+H] m/e 220.

Preparation of 1-azabicyclo[3.2.2]nonan-3-one (Int 105)

[0592] To a stirred solution of DIEA (13 mL) in acetonitrile (680 mL) atreflux temperature is added a solution of Int 104 (2.0 g, 6.0 mmol) inacetonitrile (125 mL) over a 4 h period via syringe pump. The mixture iskept at reflux temperature overnight. The mixture is concentrated invacuo and the remaining residue is partitioned between a saturatedaqueous potassium carbonate solution and CHCl₃-MeOH (90:10). The aqueouslayer is extracted with CHCl₃-MeOH (90:10), and the combined organiclayers are dried (MgSO₄), filtered and concentrated in vacuo to a brownoil. The crude product is purified by flash chromatography on silicagel. Elution with CHCl₃-MeOH—NH₄OH (95:4.5:0.5) gives 600 mg (72%) ofInt 105 as a clear solid: ¹H NMR (400 MHz, CDCl₃) δ 3.7, 3.3-3.2,3.1-3.0, 2.7, 2.3, 2.0-1.8.

Preparation of 1-azabicyclo[3.2.2]nonan-3-aminebis(4-methylbenzenesulfonate) ([3.2.2]-Amine)

[0593] To a stirred mixture of Int 105 (330 mg, 2.4 mmol) and sodiumacetate.trihydrate (670 mg, 4.8 mmol) in EtOH (6.0 mL) is addedhydroxylamine.hydrochloride (200 mg, 2.8 mmol). The mixture is stirredat rt for 10 h. The mixture is filtered and the filtrate is concentratedin vacuo to a yellow solid. To a solution of the solid (350 mg, 2.3mmol) in n-propanol (30 mL) at reflux temperature is added sodium metal(2.0 g, 87 mmol) in small portions over 30 min. Heating at reflux iscontinued for 2 h. The solution is cooled to rt and brine is added. Themixture is extracted with n-propanol, and the combined organic layersare concentrated in vacuo. The residue is taken up in CHCl₃ and theremaining solids are filtered. The filtrate is dried over anhydrousMgSO₄, filtered and concentrated in vacuo to a clear solid. To a stirredsolution of the solid (320 mg, 2.3 mmol) in EtOH (4 mL) is addedp-toluenesulfonic acid monohydrate (875 mg, 4.6 mmol). The solution iswarmed in a water bath to 45° C. for 30 min, followed by concentrationof the solvent to afford 710 mg (62%) of [3.2.2]-Amine as a white solid:¹H NMR (400 MHz, CD₃OD) δ 7.7, 7.3, 4.1-3.9, 3.6-3.4, 2.6-2.5, 2.4,2.2-2.1, 2.1-2.0, 1.9.

Resolution of Stereoisomers

[0594] The amine can be coupled to form the appropriate amides as aracemic mixture. The racemic mixture can then be resolved bychromatography using chiral columns or chiral HPLC, techniques widelyknown in the art, to provide the requisite resolved enantiomers 3(R) and3(S) of said amides.

Couplings

[0595] The following examples are provided as examples and are notintended to limit the scope of this invention to only those providedexamples and named compounds. The named compounds provided herein can bemade using procedures discussed herein, making non-critical changes andusing procedures well known to those skilled in the art. Also, the saltsmade in the examples are only exemplary and are not intended to limitthe invention. Any pharmaceutically acceptable salt can be made by oneof ordinary skill in the art. Further, the naming of specificstereoisomers is for exemplification, and is not intended to limit inanyway the scope of the invention. The invention includes the followingexamples in pure stereoisomeric form or as racemic mixtures.

EXAMPLE 1N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-5-carboxamide.hydrochloride

[0596]

[0597] 1-(2,3-Dihydrobenzofuran-5-yl)ethanone is made using a procedure,making non-critical changes, as described in Dunn, J. P.; Ackerman, N.A.; Tomolois, A. J. J. Med. Chem. 1986, 29, 2326. Similar yield (82%)and similar purity (95%) are obtained. ¹H NMR (400 MHz, CDCl₃) δ 7.89,7.83, 6.84, 4.70, 3.29, 2.58.

[0598] A mixture of 1-(2,3-dihydrobenzofuran-5-yl)ethanone (4.0 g, 25mmol) and sodium hypochlorite [160 mL of a 6.0% aqueous solution,(Clorox brand of bleach)] at 55° C. is stirred for 1 h. The mixture (nowhomogeneous) is cooled to rt and solid sodium bisulfite is added until aclear color persists. Hydrochloric acid (80 mL of a 1.0 N aqueoussolution) is added, followed by extraction with EtOAc. The organic layeris washed with brine, dried (MgSO₄), filtered, and concentrated in vacuoto afford 3.93 g (97%) of 2,3-dihydrobenzofuran-5-carboxylic acid as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 11.0-10.3, 8.00, 6.87, 4.72,3.31.

[0599] To a stirred solution of 2,3-dihydrobenzofuran-5-carboxylic acid(3.96 g, 24.1 mmol) in MeOH (200 mL) is added concentrated sulfuric acid(0.5 mL). The mixture is heated to reflux for 24 h. The mixture iscooled to rt, followed by the addition of solid sodium bicarbonate. Thereaction mixture is concentrated in vacuo, and the remaining residue ispartitioned between EtOAc and water. The aqueous layer is extracted withEtOAc, and the combined organic layers are dried (MgSO₄), filtered andconcentrated in vacuo to afford 4.22 g (98%) of methyl2,3-dihydrobenzofuran-5-carboxylate as a white solid. ¹H NMR (400 MHz,CDCl₃) δ 7.93-7.89, 6.82, 4.69, 3.86, 3.28.

[0600] To a stirred solution of methyl2,3-dihydrobenzofuran-5-carboxylate (4.2 g, 24 mmol) in anhydrousp-dioxane (150 mL) under argon atmosphere is added2,3-dichloro-5,6-dicyano-1,4-benzoquinone (6.42 g, 28 mmol). The mixtureis heated to reflux for 24 h, followed by cooling to rt. The reactionmixture is partitioned between ether and ½ saturated aqueous sodiumcarbonate solution. The organic layer is extracted several times with ½saturated aqueous sodium carbonate solution. The organic layer is washedwith water, dried over (MgSO₄), filtered, and concentrated in vacuo togive a mixture (92%) of recovered starting material methyl2,3-dihydrobenzofuran-5-carboxylate and methyl benzofuran-5-carboxylatein a ratio of 1:3. The crude product is purified by preparative HPLCusing a Chiralcel OJ column. Elution with heptane-iso-propyl alcohol,(80:20, flow rate=70 mL/min) gives 0.75 g (18%) of methyl2,3-dihydrobenzofuran-5-carboxylate as a white solid and 2.5 g (61%) ofmethyl benzofuran-5-carboxylate as a white solid. ¹H NMR for methylbenzofuran-5-carboxylate (400 MHz, CDCl₃) δ 8.40, 8.07, 7.73, 7.57,6.89, 3.99.

[0601] A stirred mixture of methyl benzofuran-5-carboxylate (1.3 g, 7.38mmol) in MeOH (51 mL) and sodium hydroxide (41 mL of a 5% aqueoussolution) is heated to 65° C. for 4 h. The mixture is cooled to rt, andMeOH is removed in vacuo. The remaining aqueous layer is extracted withCH₂Cl₂. The CH₂Cl₂ layer is discarded, and the aqueous layer isacidified to pH=1 with concentrated hydrochloric acid. The aqueous layeris extracted with CHCl₃. The organic layer is washed with water, dried(MgSO₄), filtered and concentrated in vacuo to afford 1.2 g (98%) ofbenzofuran-5-carboxylic acid as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 12.9, 8.30, 8.11, 7.92, 7.69, 7.09.

[0602] Benzofuran-5-carboxylic acid (0.16 g, 1.0 mmol) and TEA (0.8 mL,5.7 mmol) are dissolved in 10 mL THF. Diphenylphosphinic chloride (0.24g, 1.0 mmol) is added dropwise. After 0.5 h, 2S-methyl-2.2.2-Amine isadded, and the reaction is allowed to stir at RT. After 3 days, 1N NaOHis added, and the mixture is extracted with CHCl₃. The combined organiclayers are dried (MgSO₄), filtered and concentrated. The residue ispurified by chromatography (Biotage 40S, 90:9:1 CHCl₃/MeOH/NH₄OH). Thehydrochloride salt is prepared and recrystallized from MeOH/EtOAc toprovide 0.036 g (11%) of the product. HRMS (FAB) calcd for C₁₇H₂₀N₂O₂+H285.1603, found 285.1599.

EXAMPLE 2N-[exo-(4S)-1-azabicyclo[2.2.1]hept-3-yl]-1H-indole-6-carboxamide.fumarate

[0603]

[0604] To a stirred solution of 1H-indole-6-carboxylic acid (81 mg, 0.5mmol) in anhydrous DMF (10 mL) are added DIEA (265 μL, 1.52 mmol) andexo-(4S)-[2.2.1]-Amine (228 mg, 0.5 mmol). The mixture is cooled to 0°C., and HATU (190 mg, 0.5 mmol) is added in one portion. The reactionmixture is allowed to warm to rt and stir overnight. The solvent isremoved in vacuo, and the residue is partitioned between saturatedaqueous potassium carbonate solution and CHCl₃. The aqueous layer isextracted with CHCl₃ (2×). The combined organic layers are washed withbrine, dried (Na₂SO₄), filtered and concentrated in vacuo. The crudeproduct is purified by flash chromatography on silica gel. Elution withCHCl₃-MeOH—NH₄OH (89:9:1) gives the free base as a yellow solid (84 mg,66%).

[0605] To a stirred solution of the free base (84 mg, 0.33 mmol) in MeOH(5 mL) is added a warm solution of fumaric acid (38 mg, 0.33 mmol) inMeOH (5 mL). The mixture is stirred for 10 min at 50° C. The solvent isremoved in vacuo, and the remaining residue is diluted with acetone (5mL). The mixture is stirred overnight at rt. The solid is collected byfiltration, washed with acetone, and dried under high vacuum overnightgives 88 mg (72%) of Example 2 as a white solid. ¹H NMR (400 MHz, CD₃OD)δ 11.38, 8.32-8.31, 7.94, 7.58-7.50, 6.54, 6.48, 3.86-3.82, 3.15-3.10,2.97-2.89, 2.67-2.55, 1.78-1.69, 1.38-1.31.

EXAMPLE 3N-[exo-(4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzothiophene-5-carboxamide.fumarate:

[0606]

[0607] To a stirred solution of 1-benzothiophene-5-carboxylic acid (see:Badger et. al., J. Chem. Soc. 1957, 2624, 2628) (178 mg, 1.0 mmol) inanhydrous DMF (10 mL) are added DIEA (631 μL, 3.05 mmol) andexo-(4S)-[2.2.1]-Amine (456 mg, 1.0 mmol). The mixture is cooled to 0°C., and HATU (380 mg, 1.0 mmol) is added in one portion. The reactionmixture is allowed to warm to rt and stirred overnight. The solvent isremoved in vacuo, and the residue is partitioned between saturatedaqueous potassium carbonate solution and CHCl₃. The aqueous layer wasextracted with CHCl₃ (2×). The combined organic layers are washed withbrine, dried (Na₂SO₄), filtered and concentrated in vacuo. The crudeproduct is purified by flash chromatography on silica gel. Elution withCHCl₃-MeOH—NH₄OH (89:9:1) gives the free base as a light yellow oil (272mg, 100%).

[0608] To a stirred solution of the free base (272 mg, 1.0 mmol) in MeOH(5 mL) is added a warm solution of fumaric acid (116 mg, 1.0 mmol) inMeOH (5 mL). The mixture is stirred for 5 min at 50° C. The solvent isremoved in vacuo, and the remaining residue is diluted with acetone (10mL) and water (0.2 mL). The mixture is stirred overnight at rt. Thesolid is collected by filtration, washed with acetone, and dried underhigh vacuum overnight to give 300 mg (74%) of Example 3 as a whitesolid: ¹H NMR (400 MHz, CD₃OD) δ 8.38, 8.05-8.02, 7.85-7.83, 7.73-7.18,7.51-7.50, 6.71, 4.29-4.26, 3.76-3.71, 3.49-3.38, 3.28-3.23, 3.09-3.08,2.23-2.15, 1.89-1.82.

EXAMPLE 4N-[exo-(4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-5-carboxamide.4-methylbenzenesulfonate

[0609]

[0610] To a stirred solution of 1-benzofuran-5-carboxylic acid (711 mg,4.39 mmol) in anhydrous DMF (40 mL) are added DIEA (2.33 mL, 13.4 mmol)and exo-(4S)-[2.2.1]-Amine (2000 mg, 4.39 mmol). The mixture is cooledto 0° C., and HATU (1670 mg, 4.39 mmol) is added in one portion. Thereaction mixture is allowed to warm to rt and is stirred overnight. Thesolvent is removed in vacuo, and the residue is partitioned betweensaturated aqueous potassium carbonate solution and CHCl₃. The aqueouslayer was extracted with CHCl₃ (2×). The combined organic layers werewashed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo.The crude product was purified by flash chromatography on silica gel.Elution with CHCl₃-MeOH—NH₄OH (89:9:1) gives the free base as a whitesolid (1.09 g, 97.3%).

[0611] To a stirred solution of free base (1.09 g, 4.25 mmol) in MeOH(10 mL) is added a warm solution of p-toluenesulfonic acid monohydrate(809 mg, 4.25 mmol) in MeOH (10 mL). The mixture is stirred for 5 min at42° C. The solvent is removed in vacuo, and the remaining residue isdiluted with acetone (25 mL). The mixture is stirred overnight at rt.The solid is collected by filtration, washed with acetone, and driedunder high vacuum overnight to give 1.62 g (89%) of Example 4 as a whitesolid: ¹H NMR (400 MHz, CD₃OD) δ 8.19, 7.88-7.84, 7.73-7.70, 7.61-7.59,7.25-7.23, 6.95, 4.30-4.27, 3.81-3.75, 3.55-3.42, 3.29, 3.11-3.10, 2.38,2.26-2.17, 1.92-1.85.

EXAMPLE 5N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamidehydrochloride

[0612]

[0613] 3-Hydroxybenzoic acid (13.8 g, 100 mmol) is dissolved inconcentrated NH₄OH (200 mL) using an overhead stirrer and is treatedslowly drop-wise with a solution of iodine (23.4 g, 92 mmol) and KI(18.26 g, 110 mmol) in water (100 mL). The solution is stirred for 1 hat RT and then treated rapidly drop-wise with concentrated HCl (180 mL).The solid is collected via filtration, rinsed with water and driedovernight by pulling air through the solid to afford 13.1 g (54%) of3-hydroxy-4-iodobenzoic acid as a tan solid. ¹H NMR (400 MHz, DMSO-d₆):δ 7.13, 7.43, 7.80, 10.71, 12.98 ppm.

[0614] 3-Hydroxy-4-iodobenzoic acid (12.55 g, 47.5 mmol) is dissolved inMeOH (200 mL), treated slowly drop-wise with thionyl chloride (32.3 mL,443 mmol) at RT, then heated to reflux for 20 h. The mixture isconcentrated to dryness and partitioned between CH₂Cl₂ (100 mL) andsaturated NaHCO₃ (50 mL). Not all of the residue dissolves, so themixture is filtered and the solid is washed with a small amount ofCH₂Cl₂ in MeOH. The original filtrate and the organic washes arecombined, concentrated to dryness, dissolved in 10% MeOH/CH₂Cl₂ (200mL), diluted with water (50 mL) and the layers separated. The organicsare washed with saturated NaHCO₃ (2×50 mL), then water (50 mL), dried(Na₂SO₄) and concentrated to a tan solid. This solid is triturated withCH₂Cl₂ (50 mL) and filtered. The two solids are combined to afford 9.4 g(70%) of methyl 3-hydroxy-4-iodobenzoate as a beige solid. HRMS (FAB)calcd for C₈H₇IO₃+H: 278.9520, found 278.9521 (M+H)⁺.

[0615] Methyl 3-hydroxy-4-iodobenzoate (5.22 g, 18.8 mmol) is combinedwith trimethylsilylacetylene (3.71 mL, 26.3 mmol),bis(triphenylphosphine)palladium dichloride (386 mg, 0.55 mmol) andcuprous iodide (54 mg, 0.28 mmol) in THF (20 mL)/CHCl₃ (40 mL) in a dryflask, under nitrogen. Triethylamine (8.14 mL, 58.4 mmol) is added andthe mixture is heated to 50° C. for 4 h. The mixture is diluted withCHCl₃ (60 mL), washed with 5% HCl (2×40 mL), dried (MgSO₄) andconcentrated to a brown oily-solid (8.31 g). The crude material ischromatographed over a standard 90 g Biotage column, eluting with 10%EtOAc/hexane (1 L) followed by 15% EtOAc/hexane (1 L). The appropriatefractions are combined and concentrated to afford 4.22 g (91%) of methyl3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate as a yellow solid. HRMS(FAB) calcd for C₁₃H₁₆O₃SI+H: 249.0947, found 249.0947 (M+H)⁺.

[0616] Methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (3.0 g, 12.1mmol) is dissolved in 1:1 EtOH/Et₃N (30 mL), is treated with CuI (114mg, 0.6 mmol), and the reaction is warmed to 75° C. for 3 h. The mixtureis treated with DARCO and MeOH (15 mL) and heated to reflux for 1 h. Thereaction is filtered through a fine fritted-glass funnel, the filtrateis treated with 3N NaOH (24.2 ml, 72.5 mmol), and the mixture is stirredovernight at RT. The mixture is concentrated to dryness, the residue isdissolved in H₂O (20 mL), and the pH of the mixture is adjusted to 2with 12N HCl. The resulting yellow precipitate is collected, washed withwater, and is dried to give 1.83 g (93%) of benzofuran-6-carboxylic acidas a tan solid. HRMS (FAB) calcd for C₉H₆O₃+H: 163.0395, found 163.0389(M+H)⁺.

[0617] Method A:

[0618] 1-Benzofuran-6-carboxylic acid (162 mg, 1.0 mmol) is combinedwith (R)-3-aminoquinuclidine dihydrochloride (219 mg, 1.1 mmol), DEEA(522 μL, 3.0 mmol) and DMF (5 μL), cooled to 0° C., treated with HATU(380 mg, 1.0 mmol) and stirred for 18 h as the cooling bath expired. Themixture is concentrated under high vacuum and partitioned between a 1:1solution of saturated NaCl/conc. NH₄OH (10 mL) and CHCl₃ (3×10 mL). Theorganics are dried (Na₂SO₄) and concentrated to an oil (530 mg). Thecrude material is chromatographed over 11 g slurry-packed silica gel,eluting with 2% conc. NH₄OH/10% MeOH/CHCl₃. The appropriate fractionsare combined and concentrated to a dark yellow solid (274 mg). The solidis placed under high vacuum, dissolved in MeOH (5 mL), treated with 3NHCl MeOH (1 mL), stirred for 16 h, then concentrated to dryness. Theresidue is dissolved in MeOH (1 mL) and IPA (10 mL) and treated withEt₂O (˜20 mL) until turbid. The mixture is stirred for 16 h, filteredunder nitrogen and dried in a vacuum oven at 50° C. to afford 206 mg(67%) of Example 5 as an off-white solid. HRMS (FAB) calcd forC₁₆H₁₈N₂O₂+H: 271.1446, found 271.1447 (M+H)⁺.

EXAMPLE 6N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-2-methyl-1-benzofuran-6-carboxamidehydrochloride

[0619]

[0620] 4-Hydroxybenzoic acid (34.5 g, 250 mmol) is suspended in MeOH(500 mL), treated with NaI (34.5 g, 250 mmol) and NaOH (20 g, 500 mmol)and cooled to 0° C. Sodium hypochlorite (Clorox bleach) (423 mL, 250mmol) is added slowly drop-wise at 0-5° C. and the mixture is stirredfor 1 h. The mixture is treated with saturated Na₂S₂O₃ (135 mL) andwater (135 mL) and stirred overnight as the cooling bath expired. Themixture is acidified to pH 3.5 with concentrated HCl and the resultingprecipitate filtered off. The solid contained a mixture of the desiredmono-iodo product and the iodo-chloro and the bis-iodo byproducts; it isdiscarded. The filtrate is concentrated to dryness, partitioned betweenH₂O (300 mL) and EtOAc (1×500 mL, then 3×300 mL), dried (Na₂SO₄) andconcentrated to afford 59.6 g (90%) of 4-hydroxy-3-iodobenzoic acid as awhite solid. ¹H NMR (400 MHz, DMSO-d₆): δ 6.95, 7.80, 8.22 ppm.

[0621] 4-Hydroxy-3-iodobenzoic acid (59.6 g, 226 mmol) is combined with3N HCl/MeOH (276 mL, 678 mmol) and heated to 65° C. for 24 h, thenconcentrated to dryness. The residue is diluted with water, neutralizedto pH 7 with 3N NaOH and the resulting solid collected via filtration.The crude material is adsorbed onto silica gel and chromatographed over1 kg of silica gel with 50% EtOAc/hexane. Fractions containing productare combined and concentrated to a solid (47.2 g). The material isrecrystallized from EtOAc to afford 22.8 g (36%) of methyl4-hydroxy-3-iodobenzoate as a white solid. HRMS (FAB) calcd forC₈H₇IO₃+H: 278.9520, found 278.9534 (M+H)⁺.

[0622] Methyl 4-hydroxy-3-iodobenzoate (5.56 g, 20 mmol) is combinedwith trimethylsilylacetylene (3.96 mL, 28 mmol),bis(triphenylphosphine)palladium dichloride (414 mg, 0.6 mmol) andcuprous iodide (57 mg, 0.3 mmol) in THF (20 mL)/CHCl₃ (40 mL) in a dryflask, under nitrogen. TEA (8.7 mL, 62.3 mmol) is added and the mixtureheated to 50° C. for 4 h. The mixture is diluted with CHCl₃ (60 mL),washed with 5% HCl (2×40 mL), dried (MgSO₄) and concentrated to a brownsolid. The crude material is adsorbed onto silica gel andchromatographed over 200 g silica gel, eluting with 15% EtOAc/hexane (2L) followed by 20% EtOAc/hexane (1 L). Fractions are combined andconcentrated to afford 2.50 g (50%) of methyl4-hydroxy-3-[(trimethylsilyl)ethynyl]benzoate as a yellow solid. HRMS(FAB) calcd for C₁₃HI₆O₃SI+H: 249.0947, found 249.0955 (M+H)⁺.

[0623] Methyl 4-hydroxy-3-[(trimethylsilyl)ethynyl]benzoate (11 g, 44.5mmol) is combined with CuI (423 mg, 2.2 mmol) and DIA (7.1 ml, 50 mmol)in MeOH (110 mL) in a flask under nitrogen. The reaction is warmed to60° C. for 6 h, the volatiles are removed in vacuo, and the brown-greenresidue is chromatographed over 500 g silica gel (230-400 mesh) elutingwith 20% EtOAc/hexane. Two pools are isolated to provide 3.43 g (31%) ofthe early eluting methyl 2-trimethylsilylbenzofuran-5-carboxylate and2.63 g (33%) of the later eluting methyl benzofuran-5-carboxylate. Thepools are combined in MeOH (130 mL). The solution is treated with 2NNaOH (46.8 ml, 93.6 mmol), is warmed to 50° C., and is stirred for 2 h.The mixture is cooled, the volatiles are removed in vacuo, and theresidue is dissolved in water (50 mL). The pH of the mixture is adjustedto 2 with 12N HCl, is diluted with water (40 mL), and the mixture iscooled to 0° C. The off-white solid is collected, washed with water, andis dried to give 6.0 g. The solid is dried in vacuo over P₂O₅ for 18 hto give 4.6 g (99%) of benzofuran-5-carboxylic acid as an off-whitesolid. MS for C₉H₆O₃, (ED) m/z: 162 (M)⁺.

[0624] Methyl 3-hydroxy-4-iodobenzoate (2.0 g, 7.2 mmol) is dissolved inDMF (15 ml) in a dry flask under nitrogen with propargyl trimethylsilane(1.19 ml, 7.98 mmol), bis(triphenylphosphine)palladium dichloride (71mg, 0.10 mmol), copper iodide (55 mg, 0.29 mmol), and piperidine (1.14ml, 11.5 mmol). The reaction is heated at 45° C. for 7 h and thenstirred at RT overnight. The reaction mixture is diluted with EtOAc (75ml) and washed with a 50% saturated solution of 1: 1 NaCl/NaHCO₃ (4×25ml). The organic layer is dried (Na₂SO₄) and concentrated to an amberoil. The crude material is chromatographed over 100 g slurry-packedsilica gel, eluting with 20% EtOAc/hexane. The appropriate fractions arecollected and concentrated to afford 1.5 g of a mixture methyl2-methyl-benzofuran-5-carboxylate and the corresponding 2-TMS-methylderivative, neither of which is isolated independently from one another.The mixture of esters is dissolved in MeOH (15 ml) and water (1 ml) andtreated with 2N NaOH (3.15 ml, 6.3 mmol). After 2 days, the volatilesare removed in vacuo and the residue is dissolved in H₂O (5 ml). TLCindicated the presence of 2 spots, so the solution is washed with Et₂O(3×10 ml) to remove the undesired reaction component. The pH is thenadjusted to 3 with concentrated HCl and the resulting slurry isfiltered. The isolated cake is dried overnight to yield 789 mg (85%) of2-methyl-1-benzofuran-6-carboxylic acid as a pale yellow solid. MS forC₁₀H8O₃, (EI) m/z: 176 (M)⁺.

[0625] 2-Methyl-1-benzofuran-6-carboxylic acid (176 mg, 1.0 mmol) iscoupled with (R)-3-aminoquinuclidine dihydrochloride (219 mg, 1.1 mmol)and the salt is made as described in Method A with non-critical changesto afford 282 mg (88%) of Example 6 as a white solid. HRMS (FAB) calcdfor C₁₇H₂₀N₂O₂+H: 285.1603, found 285.1586 (M+H)⁺.

EXAMPLE 7N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-2-methyl-1-benzofuran-5-carboxamidehydrochloride

[0626]

[0627] Methyl 4-hydroxy-3-iodobenzoate (3.0 g, 10.8 mmol) is dissolvedin DMF (25 ml) in a dry flask under nitrogen with propargyltrimethylsilane (1.79 ml, 11.9 mmol), bis(triphenylphosphine)palladiumdichloride (106 mg, 0.15 mmol), copper iodide (82 mg, 0.4 mmol), andpiperidine (1.71 ml, 17.2 mmol). The reaction is heated at 45° C. for 7h and then at RT overnight. The reaction mixture is diluted with EtOAc(125 ml) and washed with 1:1 saturated NaCl/NaHCO₃ (4×50 ml). Theorganic is dried (Na₂SO₄) and concentrated to an oil. The crude materialis chromatographed over 100 g slurry-packed silica gel, eluting with 15%EtOAc/hexane. The fractions containing the desired product are collectedand concentrated to afford 2.4 g (85%) of intermediatemethyl-2-trimethylsilylmethyl-benzofuran-5-carboxylate as an orange oil.The oil is dissolved in MeOH (25 ml) and H₂O (3 ml) and treated with 2NNaOH (5.1 ml, 10.2 mmol). The reaction is monitored by TLC and requiredslight heating at 45° C. for 6 h. An additional amount of 2N NaOH (5.0ml, 10.0 mmol) is required to complete the hydrolysis. The volatiles areremoved in vacuo, and the residue is dissolved in Et₂O (15 ml). The pHis adjusted to 3 with 12N HCl and the resulting slurry is filtered. Theisolated cake is dried overnight to yield 1.5 g (94%) of2-methyl-1-benzofuran-5-carboxylic acid as a gray solid. ¹H NMR (400MHz, DMSO-d₆): δ 2.47, 6.70, 7.57, 7.85, 8.16, 12.81 ppm.

[0628] 2-Methyl-1-benzofuran-5-carboxylic acid (176 mg, 1.0 mmol) iscoupled with (R)-3-aminoquinuclidine dihydrochloride (219 mg, 1.1 mmol)and the salt is made according to Method A with non-critical changes toafford 273 mg (85%) of Example 7 as a white solid. HRMS (FAB) calcd forC₁₇H₂₀N₂O₂+H: 285.1603, found 285.1606 (M+H)⁺.

EXAMPLE 8N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-2-cyano-1-benzofuran-6-carboxamide

[0629]

[0630] A dried flask under nitrogen is charged with methyl3-hydroxy-4-iodobenzoate (10.0 g, 35.9 mmol), propioaldehyde diethylacetal (5.72 ml, 40.0 mmol), bistriphenylphosphine palladium diacetate(538 mg, 0.72 mmol), copper iodide (273 mg, 1.4 mmol) and piperidine(3.94 ml, 40.0 mmol) in DMF (50 ml). The mixture is stirred at 45° C.for 6 h, then at RT overnight. The reaction is diluted with EtOAc (250ml) and washed with 50% saturated 1:1 NaCl/NaHCO₃ solution (4×100 ml).The organic layer is dried (Na₂SO₄), filtered and concentrated to abrown oil. The crude material is chromatographed over 500 gslurry-packed silica, eluting with 15% EtOAc/hexane. The appropriatefractions are collected and concentrated, affording 3.22 g (32%) ofmethyl 2-(diethoxymethyl)-l-benzofuran-6-carboxylate as an orange oil.¹H NMR (400 MHz, CDCl₃): δ 1.29, 3.72, 3.96, 5.70, 6.88, 7.61, 7.95,8.20 ppm.

[0631] Methyl 2-(diethoxymethyl)-1-benzofuran-6-carboxylate (2.71 g, 9.7mmol) is treated drop-wise with formic acid (20 ml, 530 mmol) and water(5.5 ml). The reaction is stirred overnight at RT, diluted with water(50 ml), and the brown slurry is filtered. The cake is dried overnightto afford 1.86 g (94%) of methyl 2-formyl-1-benzofuran-6-carboxylate asan amber solid. ¹H NMR (400 MHz, DMSO-d₆): δ 3.91, 8.03, 8.28, 9.92 ppm.

[0632] Hydroxylamine hydrochloride (153 mg, 2.2 mmol) is free based for5 min in 2N NaOH (1.1 ml, 2.2 mmol) and added drop-wise to a solution ofmethyl 2-formyl-1-benzofuran-6-carboxylate (408 mg, 2.0 mmol) in EtOH (6ml). The reaction is stirred overnight and the volatiles are removed invacuo. The residue is suspended in water (5 ml) and the slurry isfiltered. The cake is dried overnight to afford 399 mg (91%) ofE/Z-methyl 2-[(hydroxyimino)methyl]-1-benzofuran-6-carboxylate as alight brown solid. HRMS (FAB) calcd for C₁₁H₉NO₄+H: 220.0610, found220.0602 (M+H)⁺.

[0633] E/Z-Methyl 2-[(hydroxyimino)methyl]-1-benzofuran-6-carboxylate(438 mg, 2.0 mmol) is suspended in CH₂Cl₂ (8 ml) in a dry flask undernitrogen. Pyridine (0.65 ml, 8.0 mmol) is added via syringe, and themixture is cooled to 0° C. Trifluoroacetic anhydride (0.56 ml, 4.0 mmol)is added drop-wise, and the reaction is stirred overnight, allowing theice bath to expire. The reaction is carefully quenched with saturatedNaHCO₃ (10 ml). The layers are separated and the organic layer is dried(K₂CO₃), filtered, and concentrated to a pink solid. The crude materialis chromatographed over 25 g slurry-packed silica gel, eluting with 25%EtOAc/hexane. The appropriate fractions are collected and concentratedto afford 315 mg (78%) of methyl 2-cyano-1-benzofuran-6-carboxylate as awhite solid.

[0634] Methyl 2-cyano-1-benzofuran-6-carboxylate (250 mg, 1.24 mmol) issuspended in pH=7.0 buffer (20 ml). Pig liver esterase (41 units/mg)(150 mg, 6.21 milli-equivalents) is dissolved in pH 7.0 buffer and addeddrop-wise to the suspension. The reaction is stirred vigorouslyovernight and is monitored by TLC. The mixture is filtered throughcelite, and the pH of the liquor is adjusted to 3 with concentrated HCl.The white, milky solution is filtered through a fine frit, and theresulting cake is dried overnight, yielding 246 mg (>100%, waterpresent) of 2-cyano-1-benzofuran-6-carboxylic acid as a gray solid. MS(EI) m/z: 187 (M)⁺.

[0635] 2-Cyano-1-benzofuran-6-carboxylic acid (226 mg, 1.2 mmol) iscoupled with (R)-3-aminoquinuclidine dihydrochloride (265 mg, 1.33 mmol)and the salt is made according to Method A with non-critical changes toafford 268 mg (75%) of Example 8 as a white solid. HRMS (FAB) calcd forC₁₇H₁₇N₃O₂+H: 296.1399, found 296.1398 (M+H)⁺.

EXAMPLE 9N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyano-1-benzofuran-5-carboxamidefumarate

[0636]

[0637] Methyl 4-hydroxy-3-iodo-benzoate (9.9 g, 35 mmol) is combinedwith propioaldehyde diethylacetal (5.6 ml, 39 mmol),bis(triphenylphosphine)palladium(II) chloride (523 mg, 0.7 mmol),cuprous iodide (266 mg, 1.4 mmol), and piperidine (3.9 ml, 39 mmol) inDMF (50 ml) in a dry flask under nitrogen. The reaction is warmed to 60°C. for 6 h and is stirred overnight at RT. The mixture is diluted withEtOAc (250 ml) and is washed with 2:1:1:0.1 water/brine/saturatedNaHCO₃/conc. NH₄OH (4×100 ml). The organic layer is dried (MgSO₄) and isconcentrated in vacuo to a dark oil. The crude material ischromatographed over 300 g silica gel (230-400 mesh), eluting with 15%EtOAc/hexane. The appropriate fractions are combined and concentrated toafford 5.2 g (48%) methyl 2-(diethoxymethyl)-1-benzofuran-5-carboxylateas an amber oil. HRMS (EI) calcd for C₁₅H₁₈O₅: 278.1154, found 278.1156(M)⁺.

[0638] Methyl 2-(diethoxymethyl)-1-benzofuran-5-carboxylate (2.6 g, 8.5mmol) is combined with formic acid (15 ml) and water (3.8 ml). Thereaction is stirred 6 h at RT, the volatiles are removed in vacuo, andthe residue is neutralized with 50 ml saturated NaHCO₃. The mixture isextracted with CH₂Cl₂ (4×20 ml), the organic layer is dried (K₂CO₃), andis concentrated in vacuo to provide 1.72 g (99%) of methyl2-formyl-1-benzofuran-5-carboxylate as amber flakes. HRMS (EI) calcd forC₁₁H₈O₄: 204.0423, found 204.0418 (M)⁺.

[0639] Methyl 2-formyl-1-benzofuran-5-carboxylate (1.64 g, 8.0 mmol) isdissolved in ethanol (30 ml). The solution is treated with hydroxylaminehydrochloride (614 mg, 8.8 mmol) in 2N NaOH (4.2 ml), and the reactionis stirred overnight at RT. The reaction mixture is concentrated todryness, the residue is triturated with water, collected, and dried togive 1.7 g (97%) of methyl2-[(E,Z)-(hydroxyimino)methyl]-1-benzofuran-5-carboxylate as a paleyellow solid. HRMS (EI) calcd for C₁₁H₉NO₄: 219.0531, found 219.0536(M)⁺.

[0640] Methyl 2-[(E,Z)-(hydroxyimino)methyl]-1-benzofuran-5-carboxylate(1.65 g, 7.53 mmol) is dissolved in CH₂Cl₂ (40 ml) in a dry flask undernitrogen. The solution is treated with pyridine (2.5 ml, 30.1 mmol)followed by trifluoroacetic anhydride (2.10 ml, 15.1 mmol), and thereaction is stirred 4 h at RT. The reaction mixture is washed with 5%aqueous HCl (100 ml) followed by saturated NaHCO₃ (100 ml), the organiclayer is dried (K₂CO₃), and is concentrated in vacuo to a pale yellowsolid. The crude material is chromatographed over 50 g silica gel(230-400 mesh) eluting with 10% EtOAc/hexane. The appropriate fractionsare combined and concentrated in vacuo to give 700 mg (44%) of methyl2-cyano-1-benzofuran-5-carboxylate as a white solid. ¹H NMR (300 MHz,CDCl₃): δ 3.98, 7.55, 7.60, 8.23, 8.44 ppm.

[0641] Methyl 2-cyano-1-benzofuran-5-carboxylate (126 mg, 0.62 mmol ) issuspended in pH 7.0 buffer (7 ml). Pig Liver Esterase (41 units/mg) (76mg, 3.13 milli-equivalents) is dissolved in pH 7.0 buffer (3 ml) andadded drop-wise to the suspension. The reaction is stirred vigorouslyovernight and monitored by TLC. The mixture is filtered through celite,and the pH of the liquor is adjusted to 3 with concentrated HCl. Thewhite, milky solution is filtered through a fine frit, and the resultingcake is dried overnight, yielding 122 mg (>100%, water present) of2-cyano-1-benzofuran-5-carboxylic acid as a crunchy, tan solid. ¹H NMR(400 MHz, DMSO-d₆): δ 7.85, 8.16, 8.21, 8.45 ppm.

[0642] 2-Cyano-1-benzofuran-5-carboxylic acid (129 mg, 0.7 mmol) iscoupled with (R)-3-aminoquinuclidine dihydrochloride (151 mg, 0.75 mmol)according to Method A except that the free base is dissolved in methanol(1 ml) and EtOAc (8 ml). Fumaric acid (41 mg, 0.37 mmol) is addedportionwise, and the mixture stirred overnight. The volatiles areremoved in vacuo, to afford 123 mg (43%) of Example 9 as a white solid.MS (EI) m/z: 295 (M)⁺.

EXAMPLE 10N-6-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2,6-dicarboxamide

[0643]

[0644] Methyl 2-formyl-1-benzofuran-6-carboxylate (1.23 g, 6.0 mmol) isdissolve in DMSO (12 ml). KH₂PO₄ (229 mg, 1.68 mmol) in H₂O (2 ml) andNaClO₂ (80%, 949 mg, 8.4 mmol) in H₂O (12 ml) are added drop-wise to thesolution, and the reaction is stirred over the weekend at RT. The pH isadjusted to 10 with 2N NaOH and the mixture is extracted with Et₂O (3×50ml). The pH is adjusted again to 3 with concentrated HCl and the slurryis filtered. The cake is dried overnight, yielding 1.07 g (81%) of6-(methoxycarbonyl)-1-benzofuran-2-carboxylic acid as an ivory solid.HRMS (FAB) calcd for C₁₁H₈O₅+H: 221.0450, found 221.0436 (M+H)⁺.

[0645] 6-(Methoxycarbonyl)-1-benzofuran-2-carboxylic acid (220 mg, 1.0mmol) is combined with HATU (570 mg, 1.5 mmol) in DMF (4 mL). Themixture is treated portionwise with DIEA (350 μL, 2.0 mmol) and NH₄Cl(183 mg, 3.4 mmol) and stirred for 3 h. The mixture is diluted withsaturated NaCl (50 mL) and extracted with EtOAc (3×20 mL). The combinedorganics are washed with 2N HCl (2×10 mL), followed by water (2×10 mL),saturated NaHCO₃ (2×10 mL) and additional H₂O (2×10 mL) then dried(Na₂SO₄) and concentrated to afford 177 mg (81%) of methyl2-(aminocarbonyl)-1-benzofuran-6-carboxylate as an orange-brown solid.HRMS (FAB) calcd for C₁₁H₉NO₄+H: 220.0610, found 220.0603 M+H)⁺.

[0646] Methyl 2-(aminocarbonyl)-1-benzofuran-6-carboxylate(164 mg, 0.75mmol) is dissolved in MeOH (5 mL) and water (1 mL), treated drop-wisewith 2N NaOH (450 μL, 0.9 mmol) and monitored by TLC. The volatiles areremoved in vacuo, and the resulting tan solid is dissolved in water (5mL) and acidified to pH 3 with concentrated HCl. The resulting solid iscollected via filtration and dried in a vacuum oven with heat 50° C. toafford 142 mg (93%) of 2-(aminocarbonyl)-1-benzofuran-6-carboxylic acidas an orange solid. HRMS (EI) calcd for C₁₀H₇NO₄: 205.0375, found205.0378 (M)⁺.

[0647] 2-(Aminocarbonyl)-1-benzofuran-6-carboxylic acid (131 mg, 0.64mmol) is coupled with (R)-3-aminoquinuclidine dihydrochloride (140 mg,0.7 mmol) according to Method A to afford 174 mg (87%) of Example 10 asa pale yellow solid. HRMS (FAB) calcd for C₁₇H₁₉N₃O₃+H: 314.1505, found314.1502 (M+H)⁺.

EXAMPLE 11N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-6-carboxamide.fumarate

[0648]

[0649] 1-Benzothiophene-6-carboxylic acid [see: Badger et al. J. Chem.Soc. 1957, 2624, 2628] is coupled with (R)-3-aminoquinuclidinedihydrochloride according to Method C making non-critical changes togive the free base as a white solid (260 mg, 95%) and Example 11 as awhite solid (260 mg, 71%): ¹H NMR (400 MHz, CD₃OD) δ 8.48, 7.95, 7.87,7.80, 7.48, 6.71, 4.52-4.45, 3.89-3.80, 3.50-3.25, 2.41-2.36, 2.33-2.23,2.15-2.08, 2.00-1.88.

EXAMPLE 12N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-5-carboxamide.fumarate

[0650]

[0651] 1-Benzothiophene-5-carboxylic acid is coupled with(R)-3-aminoquinuclidine dihydrochloride according to Method C makingnon-critical changes to give the free base as a white solid (256 mg,90%) and Example 12 as a white solid (260 mg, 71%): ¹H NMR (400 MHz,CD₃OD) δ 8.40, 8.03, 7.84, 7.71, 7.50, 6.71, 4.50-4.45, 3.90-3.82,3.52-3.28, 2.40-2.36, 2.33-2.21, 2.16-2.08, 2.01-1.90.

EXAMPLE 13N′5′-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2,5-dicarboxamide

[0652]

[0653] Methyl 2-cyano-1-benzofuran-5-carboxylate (426 mg, 2.0 mmol) isdissolved in MeOH (10 ml). The solution is cooled to 0° C., is treatedwith LiOH monohydrate (168 mg, 4.0 mmol) in H₂O (4 ml), and the reactionis stirred 6 h at RT. The volatiles are removed in vacuo and the residueis dissolved in H₂O (10 ml). The pH of the mixture is adjusted to 1.9with 12N HCl, the white solid is collected, washed with water, and isdried to give 401 mg (97%) of2-(aminocarbonyl)-1-benzofuran-5-carboxylic acid as an off-white solid.MS (EI) calcd for C₁₀H₇NO₄: 205.0375, found 205.0369 (M)⁺.

[0654] 2-(Aminocarbonyl)-1-benzofuran-5-carboxylic acid (350 mg, 1.7mmol) is coupled with (R)-3-aminoquinuclidine dihydrochloride (374 mg,1.9 mmol) according to Method A to afford 120 mg (23%) of Example 13 aswhite solid. HRMS (ESI) calcd for C₁₇H₁₉N₃O₃+H: 314.1505, found 314.1513(M+H)⁺.

EXAMPLE 142-Acetyl-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamidehydrochloride

[0655]

[0656] Methyl 2-formyl-1-benzofuran-6-carboxylate (750 mg, 3.67 mmol) isdissolved in anhydrous THF (30 ml) in a dry flask under nitrogen andcooled to 0° C. Methyl magnesium bromide (2.6 ml, 3.67 mmol) is addedvia syringe, and the reaction is stirred overnight, allowing the icebath to expire. The reaction is quenched with 5% HCl (70 ml) andextracted with CH₂Cl₂ (3×25 ml). The combined organics are dried(MgSO₄), filtered, and concentrated to a yellow oil. The crude materialis chromatographed over 100 g slurry-packed silica gel, eluting with 35%EtOAc/hexane. The appropriate fractions are collected and concentratedto afford 412 mg (51%) of methyl2-(1-hydroxyethyl)-1-benzofuran-6-carboxylate as a yellow oil thatsolidified upon standing. MS for C₁₂H]₂O₄, (EI) m/z: 220 (M)⁺.

[0657] Oxalyl chloride (0.1 ml, 1.15 mmol) is dissolved in CH₂Cl₂ (2 ml)in a dry flask under nitrogen and cooled to −78° C. DMSO (0.16 ml, 2.3mmol) is added drop-wise, and the mixture stirred for 30 min, whilemaintaining the temperature. Methyl2-(1-hydroxyethyl)-1-benzofuran-6-carboxylate (220 mg, 1.0 mmol) isdissolved in CH₂Cl₂ (2 ml) and added drop-wise to the mixture, and thesolution stirred for 1 h at −78° C. TEA (0.69 ml, 5.0 mmol), is addeddrop-wise and the reaction is stirred for an additional 30 min. Thereaction is then warmed to 0° C. and stirred for another 30 min. Thereaction is washed with saturated NaHCO₃ (40 ml), and the organics aredried (K₂CO₃), filtered, and concentrated to a yellow solid. The crudematerial is chromatographed over 25 g slurry-packed silica gel, elutingwith 20% EtOAc/hexane. The appropriate fractions are collected andconcentrated to afford 174 mg (80%) of methyl2-acetyl-1-benzofuran-6-carboxylate as a pale yellow solid. HRMS (FAB)calcd for C₁₂H₁₀O₄+H: 219.0657, found 219.0667 (M+H)⁺.

[0658] Methyl 2-acetyl-1-benzofuran-6-carboxylate (155 mg, 0.71 mmol) isdissolved in MeOH (3 ml) and H₂O (0.5 ml). 2N NaOH (0.39 ml, 0.78 mmol)is added drop-wise, and the reaction is stirred overnight. The volatilesare removed in vacuo, and the residue is dissolved in H₂O (3 ml).Concentrated HCl is used to adjust the pH to 3, and the resultingprecipitate is isolated via filtration and dried overnight to afford 135g (93%) of 2-acetyl-1-benzofuran-6-carboxylic acid as a yellow solid. MSfor C₁₁H₈O₄, (ESI−) m/z: 202.7 (M−H)⁻.

[0659] 2-Acetyl-1-benzofuran-6-carboxylic acid (130 mg, 0.64 mmol) iscoupled with (R)-3-aminoquinuclidine dihydrochloride (140 mg, 0.70 mmol)and salt made according to Method A with non-critical variations toafford 176 mg (79%) of Example 14 as a yellow solid. HRMS (FAB) calcdfor C₁₈H₂₀N₂O₃+H: 313.1552, found 313.1552 (M+H)⁺.

EXAMPLE 15N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-2-formyl-1-benzofuran-6-carboxamide

[0660]

[0661] Methyl 2-(diethoxymethyl)-1-benzofuran-6-carboxylate (417 mg, 1.5mmol) is dissolved in MeOH (8 ml) and H₂O (2 ml). 2N NaOH (0.9 ml, 1.8mmol) is added drop-wise, and the reaction is stirred for 4 days. Thevolatiles are removed in vacuo and the residue is dissolved in H₂O (2ml). Concentrated HCl is used to adjust the pH to 3, and the resultingprecipitate is isolated via filtration and dried overnight to afford 410mg (>100%, water present) of2-(diethoxymethyl)-1-benzofuran-6-carboxylic acid as a brown solid. ¹HNMR (400 MHz, CDCl₃): δ 1.29, 3.72, 6.9, 7.66, 8.04, 8.29 ppm.

[0662] 2-(Diethoxymethyl)-1-benzofuran-6-carboxylic acid (264 mg, 1.0mmol) is coupled with (R)-3-aminoquinuclidine dihydrochloride (219 mg,1.1 mmol) and salt made according to Method A with non-critical changesto afford 286 mg (70%) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-(diethoxymethyl)-1-benzofuran-6-carboxamidehydrochloride as a white solid. HRMS (FAB) calcd for C₂₁H₂₈N₂O₄+H:373.2127, found 373.2121 (M+H)⁺.

[0663]N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-2-(diethoxymethyl)-1-benzofuran-6-carboxamidehydrochloride (100 mg, 0.24 mmol) is dissolved in formic acid (1 ml, 26mmol), treated drop-wise with H₂O (0.25 ml) and stirred overnight. Thevolatiles are removed in vacuo, the residue treated carefully withsaturated NaHCO₃ (5 ml) and stirred for 15 min. The precipitate isisolated via filtration and the cake dried overnight to yield 58 mg(80%) of Example 15 as a light tan solid. HRMS (FAB) calcd forC₁₇H₁₈N₂O₃+H: 299.1396, found 299.1402 (M+H)⁺.

EXAMPLE 16N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-benzofuran-6-carboxamidehydrochloride

[0664]

[0665] Methyl 3-hydroxy-4-iodobenzoate (2.0 g, 7.2 mmol) is dissolved inDMF (25 ml) in a dry flask under nitrogen. Allyl bromide (0.65 ml, 7.55mmol) is added drop-wise, followed by the careful addition of 60% NaH(303 mg, 7.55 mmol). The reaction is stirred overnight at RT and then isdiluted with H₂O (30 ml). The mixture is extracted with EtOAc (3×30 ml),and the combined organics are washed with 50% saturated NaCl (4×25 ml),dried (MgSO₄), filtered, and concentrated under high vacuum to an oilthat solidified upon standing. The volatiles are removed in vacuo toobtain 2.28 g (100%) of methyl 3-(allyloxy)-4-iodobenzoate as a tansolid. HRMS (FAB) calcd for C₁₁H₁₁IO₃+H: 318.9833, found 318.9831(M+H)⁺.

[0666] Methyl 3-(allyloxy)-4-iodobenzoate (2.0 g, 6.28 mmol) isdissolved in DMF (15 ml), treated with Pd(OAc)₂ (71 mg, 0.31 mmol),Na₂CO₃ (1.67 g, 15.7 mmol), sodium formate (427 mg, 6.28 mmol), andn-Bu₄NCl.H₂O (1.92 g, 6.92 mmol) and stirred at 80° C. for 2 days. Themixture is then filtered, the liquor is diluted with EtOAc (75 ml) andwashed with 50% saturated NaCl (4×25 ml) followed by 5% HCl (25 ml). Theorganic layer is dried (Na₂SO₄), filtered, and concentrated to a brownoil. The crude material is chromatographed over 50 g slurry-packedsilica gel, eluting with 20% EtOAc/hexane. The appropriate fractions arecombined and concentrated to afford 797 mg (67%) of methyl3-methyl-1-benzofuran-6-carboxylate as a pale oil. HRMS (FAB) calcd forC₁₁H₁₀O₃+H: 191.0708, found 191.0714 (M+H)⁺.

[0667] Methyl 3-methyl-1-benzofuran-6-carboxylate (720 mg, 3.78 mmol) isdissolved in MeOH (10 ml), treated with 2N NaOH (2.27 ml, 4.5 mmol) andstirred overnight. The volatiles are removed in vacuo, the residue isdissolved in H₂O (5 ml) and the pH is adjusted to 3 with concentratedHCl. The mixture is stirred overnight and the resulting solid isfiltered to afford 545 mg (82%) of 3-methyl-1-benzofuran-6-carboxylicacid as a white solid. HRMS (FAB) calcd for C₁₀H₈O₃+H: 177.0552, found177.0551 (M+H)⁺.

[0668] 3-Methyl-1-benzofuran-6-carboxylic acid (176 mg, 1.0 mmol) iscoupled with (R)-3-aminoquinuclidine dihydrochloride (219 mg, 1.1 mmol)and salt made according to Method A with non-critical variations toafford 244 mg (76%) of Example 16 as a white solid. HRMS (FAB) calcd forC₁₇H₂₀N₂O₂+H: 285.1603, found 285.1616 (M+H)⁺.

EXAMPLE 17N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-benzofuran-5-carboxamidehydrochloride

[0669]

[0670] Methyl 4-hydroxy-3-iodobenzoate (1.85 g, 6.65 mmol) is dissolvedin anhydrous DMF (15 mL) in a dry flask under nitrogen, treated with NaH(60% dispersion in oil, 265 mg, 6.65 mmol) and stirred for 1 h at RT.Allyl bromide (633 μL, 7.32 mmol) is added and the mixture is stirredfor 16 h. The mixture is concentrated and the residue is partitionedbetween EtOAc (25 mL) and H₂O (25 mL). The organic layer is washed witha 50% saturated mixture of 1:1 NaC/NaHCO₃ (2×10 mL), dried (MgSO₄) andconcentrated to a yellow oil which solidified to a white solid uponstanding (2.12 g). The crude material is chromatographed over 100 gslurry-packed silica gel, eluting with 10% EtOAc/hexane. The appropriatefractions are combined and concentrated to afford 1.27 g (60%) of methyl4-(allyloxy)-3-iodobenzoate as a colorless oil which solidified onstanding. MS for C₁₁H₁₁IO₃ (ED) m/z: 318 (M)⁺.

[0671] Methyl 4-(allyloxy)-3-iodobenzoate (587 mg, 1.84 mmol) iscombined with Pd(OAc)₂ (5%, 20 mg, 0.1 mmol), Na₂CO₃ (487 mg, 4.6 mmol),sodium formate (125 mg, 1.8 mmol) and n-Bu₄NCl.H₂O (561 mg, 2.0 mmol) inDMF (5 mL) and heated to 80° C. for 2 days. The mixture is concentratedunder high vacuum and partitioned between 50% saturated NaCl (10 mL) andCH₂Cl₂ (4×10 mL). The combined organics are washed with 5% HCl (10 mL),dried (Na₂SO₄) and concentrated to a brown oil. The crude material ischromatographed over 15 g slurry-packed silica gel, eluting with 15%EtOAc/hexane. The appropriate fractions are combined and concentrated toafford 153 mg (44%) of methyl 3-methyl-1-benzofuran-5-carboxylate as awhite solid. HRMS (FAB) calcd for C₁₁H₁₀O₃+H: 191.0708, found: 191.0705(M+H)⁺.

[0672] Methyl 3-methyl-1-benzofuran-5-carboxylate (365 mg, 1.9 mmol) isdissolved in MeOH (7 mL), diluted with H₂O (3.5 mL) and treated with 3NNaOH (1.41 mL, 4.2 mmol). The mixture is diluted with MeOH (3.5 mL) tohomogeneity, stirred at RT for 2.5 days then concentrated to dryness.The residue is dissolved in H₂O (5 mL) and acidified to pH 2 withconcentrated HCl. The resulting solid is filtered and dried in a vacuumoven at 40° C. for 18 h to afford 321 mg (95%) of3-methyl-1-benzofuran-5-carboxylic acid as a white solid. HRMS (FAB)calcd for C₁₀H₈O₃+H: 177.0552, found: 177.0553 (M+H)⁺.

[0673] 3-Methyl-1-benzofuran-5-carboxylic acid (156 mg, 0.88 mmol) iscoupled with (R)-3-aminoquinuclidine dihydrochloride (193 mg, 0.97 mmol)and salt made according to Method A with non-critical variations toafford 235 mg (83%) of Example 17 as a white solid. HRMS (FAB) calcd forC₁₇H₂₀N₂O₂+H: 285.1603, found 285.1613 (M+H)⁺.

EXAMPLE 18N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-isopropyl-1-benzofuran-5-carboxamidehydrochloride

[0674]

[0675] Methyl 4-hydroxy-3-iodobenzoate (6.0 g, 21.5 mmol) is dissolvedin DMF (35 ml) in a dry flask under nitrogen and cooled to 0° C. NaH(60% dispersion in oil, 860 mg, 21.5 mmol) is added portion-wise and thereaction is stirred for 1 h, allowing the ice bath to expire. Themixture is then treated with 1-chloro-3-methyl-2-butene (2.67 ml, 23.7mmol) and NaI (323 mg, 2.15 mmol), and the reaction is stirred for 18 hat RT. The mixture is diluted with EtOAc (150 ml) and washed with 1:1saturated NaCl/NaHCO₃ (100 ml). The organic layer is dried (MgSO₄),concentrated to an oil and chromatographed over 700 g slurry-packedsilica gel, eluting with 15% EtOAc/hexane. The appropriate fractions arecollected and concentrated to afford 5.13 g of a pale oil. Thedimethylallyl ether is dissolved in DMF (40 ml) and treated successivelywith Pd(OAc)₂ (165 mg, 0.74 mmol), Na₂CO₃ (3.9 g, 36.8 mmol), sodiumformate (1.0 g, 14.7 mmol), and n-Bu₄NCl.H₂O (4.5 g, 16.2 mmol). Themixture is stirred for 2 days at 80° C., then diluted with EtOAc (200ml) and washed with 50% saturated NaCl (3×75 ml) followed by 5% HCl (75ml). The organic layer is dried (MgSO₄), filtered and concentrated to abrown oil. The crude material is chromatographed over 250 gslurry-packed silica gel, eluting with 10% EtOAc/hexane. The appropriatefractions are collected and concentrated to afford 1.33 g (28% over 2steps) of methyl 3-isopropyl-1-benzofuran-5-carboxylate as an oil. HRMS(FAB) calcd for C₁₃H₁₄O₃+H: 219.1021, found 219.1021 (M+H)⁺.

[0676] Methyl 3-isopropyl-1-benzofuran-5-carboxylate (1.20 g, 5.51 mmol)is dissolved in MeOH (20 ml) and water (4 ml), treated drop-wise with 2NNaOH (3.3 ml, 6.6 mmol) and stirred at RT for 2 days, then at 40° C. for4 h. The volatiles are removed in vacuo, the residue is dissolved inwater (10 ml) and the pH is adjusted to 3 with concentrated HCl. Theresulting precipitate is isolated via filtration and dried overnight toafford 1.08 g (97%) of 3-isopropyl-1-benzofuran-5-carboxylic acid as awhite solid. MS (ESI−) for C₁₂H₁₂O₃ m/z: 203.0 (M−H)⁻.

[0677] 3-Isopropyl-1-benzofuran-5-carboxylic acid (204 mg, 1.0 mmol) iscoupled with (R)-3-aminoquinuclidine dihydrochloride (219 mg, 1.1 mmol)and salt made according to Method A with non-critical variations toafford 313 mg (90%) of Example 19 as a white solid. HRMS (FAB) calcd forC₁₉H₂₄N₂O₂+H: 313.1916, found 313.1913 (M+H)⁺.

EXAMPLE 19N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-5-carboxamide.fumarate

[0678]

[0679] 1-Benzofuran-5-carboxylic acid is coupled with(R)-3-aminoquinuclidine dihydrochloride according to Method C makingnon-critical changes to give the free base as a white solid (1.1 g, 95%)and Example 19 as a white solid (1.5 g, 92%): ¹H NMR (400 MHz, CD₃OD) δ8.20, 7.88, 7.85, 7.61, 6.97, 6.70, 4.50-4.43, 3.89-3.80, 3.50-3.23,2.40-2.34, 2.32-2.21, 2.16-2.08, 2.00-1.89.

EXAMPLE 20N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-chloro-1-benzofuran-6-carboxamidehydrochloride

[0680]

[0681] Methyl 3-hydroxy-4-[(trimethylsilyl)ethynyl]benzoate (4.15 g,16.7 mmol) is dissolved in MeOH (45 ml) and treated with DIA (2.34 ml,16.7 mmol). Copper iodide (159 mg, 0.84 mmol) is added portion-wise andthe reaction is heated at 75° C. for 3 h. DARCO (2 g) is added and thereaction is stirred at 95° C. for an additional 2 h, then overnight atRT. The reaction is filtered, concentrated to a brown oil and the crudematerial is chromatographed over 300 g slurry-packed silica gel, elutingwith 10% EtOAc/hexane. The appropriate fractions are collected andconcentrated to afford 2.05 g (70%) of methyl 1-benzofuran-6-carboxylateas an orange crystalline solid. ¹H NMR (400 MHz, CDCl₃) δ 3.97, 6.84,7.65, 7.78, 7.98, 8.22 ppm.

[0682] Methyl 1-benzofuran-6-carboxylate (1.90 g, 10.7 mmol) isdissolved in Et₂O (50 ml) and cooled to 0° C. Chlorine gas is bubbled infor 5 min, and the reaction is stirred over the weekend, allowing theice bath to expire. The volatiles are removed in vacuo, and the crudematerial is chromatographed over 300 g slurry-packed silica gel, elutingwith 10% EtOAc/hexane. The appropriate fractions are collected andconcentrated to afford 906 mg (34%) of cis-methyl2,3-dichloro-2,3-dihydro-1-benzofuran-6-carboxylate as a pale oil. Asecond pool of fractions is collected and concentrated to afford 1.25 g(47%) of trans-methyl2,3-dichloro-2,3-dihydro-1-benzofuran-6-carboxylate and as a yellow oil.

[0683] trans-isomer: ¹H NMR (400 MHz, CDCl₃): δ 3.93, 5.47, 6.53, 7.56,7.69, 7.85 ppm.

[0684] cis-isomer: ¹H NMR (400 MHz, CDCl₃): δ 3.94, 5.68, 6.69,7.49,7.63, 7.85 ppm

[0685] trans-Methyl 2,3-dichloro-2,3-dihydro-1-benzofuran-6-carboxylate(58 mg, 0.23 mmol) is dissolved in EtOH (2 ml), treated with K₂CO₃ (187mg, 1.35 mmol) and stirred at RT overnight. The mixture is concentratedto dryness, the residue is dissolved in 50% saturated NaCl (10 ml) andextracted with CH₂Cl₂ (3×10 ml). The combined organics are dried(K₂CO₃), filtered, and concentrated in vacuo to a yellow oil. The crudematerial is chromatographed over 10 g slurry-packed silica gel, elutingwith 25% EtOAc/hexane. The appropriate fractions are combined andconcentrated to afford 30 mg (58%) of ethyl3-chloro-1-benzofuran-6-carboxylate as a yellow oil. ¹H NMR (400 MHz,CDCl₃): δ 1.44, 4.43, 7.66, 7.79, 8.07, 8.21 ppm.

[0686] Ethyl 3-chloro-1-benzofuran-6-carboxylate (110 mg, 0.49 mmol) isdissolved in MeOH (3 ml) and water (0.75 ml), treated drop-wise with 2NNaOH (0.27 ml, 0.54 mmol) and stirred overnight at RT. The volatiles areremoved in vacuo, the residue is dissolved in water (3 ml) and the pH isadjusted to 3 with concentrated HCl. The resulting solid is filtered anddried overnight in a vacuum oven to afford 88 mg (92%) of3-chloro-1-benzofuran-6-carboxylic acid as a white solid. MS forC₉H₅ClO₃ (ED) m/z: 196(M)⁺.

[0687] 3-Chloro-1-benzofuran-6-carboxylic acid (75 mg, 0.38 mmol) iscoupled with (R)-3-aminoquinuclidine dihydrochloride (84 mg, 0.42 mmol)and salt made according to Method A with non-critical variations toafford 116 mg (89%) of Example 20 as an ivory-colored solid. HRMS (FAB)calcd for C₁₆H₁₇ClN₂O₂+H: 305.1057, found 305.1043 (M+H)⁺.

EXAMPLE 21N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-5-carboxamide

[0688]

[0689] Methyl 4-hydroxy-3-[(trimethylsilyl)ethynyl]benzoate (11 g, 44.5mmol) is combined with DIA (7.1 ml, 50 mmol) and cuprous iodide (423 mg,2.2 mmol) in 100 ml MeOH in a flask under nitrogen. The reaction iswarmed to 60° C. for 6 h, the volatiles are removed in vacuo, and thebrown-green residue is chromatographed over 500 g silica gel (230-400mesh) eluting with 20% EtOAc/hexane. The appropriate fractions arecombined and concentrated to give 2.63 g (34%) of methylbenzofuran-5-carboxylate as a pale oil which crystallized on standing.¹H NMR (300 MHz, CDCl₃): δ 3.95, 6.86, 7.53, 7.70, 8.03, 8.36 ppm.

[0690] Methyl benzofuran-5-carboxylate (1.74 g, 9.9 mmol) is dissolvedin CH₂Cl₂ (50 mL), layered with saturated NaHCO₃ (75 mL) using very slowmagnetic stirring so that the two layers are not mixed and treated withBr₂ (3.1 mL, 59.1 mmol). The bi-phasic mixture is stirred slowly for 2h, then vigorously for 1 h. The layers are separated and the aqueouslayer is extracted with CH₂Cl₂ (2×50 mL). The organics are dried(Na₂SO₄) and concentrated under reduced pressure without heat. Theresidue is dissolved in MeOH (100 mL), treated with K₂CO₃ (8.17 g, 59.1mmol) and stirred at RT for 18 h. The mixture is concentrated todryness, partitioned between 50% saturated NaHCO₃ (75 mL) and EtOAc(2×75 mL) and the organics are dried (Na₂SO₄) and concentrated in vacuo.The crude material (2.21 g) is adsorbed onto silica gel (4.5 g)chromatographed over 90 g slurry-packed silica gel, eluting with 8%EtOAc/hexane then 15% EtOAc/hexane. The appropriate fractions arecombined and concentrated to afford 1.88 g (75%) of methyl3-bromo-1-benzofuran as a white solid. ¹H NMR (300 MHz, CDCl₃): δ 3.99,7.55, 7.74, 8.11, 8.31 ppm.

[0691] Methyl benzofuran-5-carboxylate (667 mg, 3.8 mmol) is dissolvedin 20 ml CH₂Cl₂ in a flask under nitrogen. The solution is treated withBr₂ (1.2 ml, 22.8 mmol), is layered with 20 ml saturated NaHCO₃, and thereaction is stirred gently for 2 h at RT. The reaction is stirredvigorously for 30 min, the layers are separated, and the organic layeris concentrated in vacuo to an amber oil. The residue is dissolved in 30ml EtOH, the solution is treated with anhydrous K₂CO₃ (3.15 g, 22.8mmol), and the reaction is stirred vigorously overnight. The insolublematerial is removed by filtration and the filtrate is diluted with 3 ml3N NaOH and the mixture is stirred 3 h at RT. The mixture isconcentrated in vacuo, the residue is dissolved in 10 ml H₂O, and the pHof the solution is adjusted to 2 with 10% aqueous HCl. The precipitateis collected, washed with water, and is dried to afford 880 mg (96%) of3-bromobenzofuran-5-carboxylic acid as an off-white solid. HRMS (FAB)calcd for C₉H₅BrO₃+H: 240.9501, found 240.9505 (M+H)⁺.

[0692] 3-Bromo-1-benzofuran-5-carboxylic acid (241 mg, 1.0 mmol) iscoupled with (R)-3-aminoquinuclidine dihydrochloride (219 mg, 1.1 mmol)according to Method A to afford 280 mg (80%) of Example 21 as anoff-white solid. HRMS (ESI) calcd for Cl₆H₁₇BrN₂O₂+H: 349.0552, found349.0555 (M+H)⁺.

EXAMPLE 22N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-ethynyl-1-benzofuran-5-carboxamide

[0693]

[0694]N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-5-carboxamide(350 mg, 1.0 mmol) is combined with bis(benzonitrile)palladiumdichloride (57 mg, 0.15 mmol), cuprous iodide (19 mg, 0.10 mmol),tri(t-butyl)phosphine (658 μL, 0.325 mmol), trimethylsilylacetylene (170μL, 1.2 mmol), and DIA (168 μL, 1.2 mmol) in dioxane (3 ml) in a dryflask under nitrogen. The reaction is stirred overnight at RT, isdiluted with EtOAc (25 ml), is washed with 1:1:0.1 NaCl/water/conc.NH40H (4×25 ml), and the organic layer is dried (K₂CO₃). The volatilesare removed in vacuo and the residue is chromatographed over 30 g silicagel (230-400 mesh) eluting with 7% MeOH/CHCl₃+1% conc. NH₄OH. Theappropriate fractions are combined and concentrated to afford 268 mg(73%) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-[(trimethylsilyl)ethynyl]-1-benzofuran-5-carboxamideas a pale foam. HRMS (ESI) calcd for C₂₁H₂₆N₂O₂SI+H: 367.1841, found367.1852 (M+H)⁺.

[0695]N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-[(trimethylsilyl)ethynyl]-1-benzofuran-5-carboxamide(255 mg, 0.70 mmol) is dissolved in MeOH (6 ml). The solution is treatedwith saturated NaHCO₃ (2 ml) and the reaction is stirred overnight atRT. The volatiles are removed in vacuo and the residue ischromatographed over 30 g silica gel (230-400 mesh) eluting with 8%MeOH/CHCl₃+1% conc. NH₄OH. The appropriate fractions are combined andconcentrated to give 190 mg of a yellow foam. The foam is crystallizedfrom Et₂O to provide 138 mg (67%) of Example 22 as a pale yellow solid.HRMS (ESI) calcd for C₁₈H₁₈N₂O₂ +H: 295.1446, found 295.1458 (M+H)⁺.

EXAMPLE 23N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-5-carboxamide

[0696]

[0697] Methyl 3-bromobenzofuran-5-carboxylate (750 mg, 2.94 mmol) iscombined with bis(benzonitrile)palladium dichloride (169 mg, 0.44 mmol),cuprous iodide (19 mg, 0.10 mmol), tri-t-butylphosphine ((10% in hexane)1.92 ml, 0.95 mmol), and propyne (2 ml, 35 mmol) in 7 ml dry dioxane in15 ml screw cap pressure tube under nitrogen. The mixture is treatedwith DIA (494 μL, 3.6 mmol), is stirred overnight at RT, and is dilutedwith 50 ml EtOAc. The reaction is washed with 4×25 ml 1:1:0.1H₂O/brine/conc. NH₄OH, the organic layer is dried (MgSO₄), and thevolatiles are removed in vacuo. The crude material is chromatographedover 50 g silica gel (230-400 mesh) eluting with 12% EtOAc/hexane. Theappropriate fractions are combined and concentrated to give 460 mg (73%)of methyl 3-prop-1-ynyl-1-benzofuran-5-carboxylate as a pale solid. MSfor C₁₃H₁₀O₃ (EI) m/z (rel. intensity): 214 (M)⁺.

[0698] Methyl 3-prop-1-ynyl-1-benzofuran-5-carboxylate (388 mg, 1.81mmol) is dissolved in 10 ml MeOH. The solution is treated with 2N NaOH(2.3 ml, 4.6 mmol) followed by 2 ml H₂O and the reaction is stirredovernight at RT. The reaction is concentrated to dryness, the residue isdissolved in 9 ml H₂O, and the pH is adjusted to 3 with 10% aqueous HCl.The precipitate is collected, washed with H₂O, and is dried to afford356 mg (98%) of 3-prop-1-ynyl-1-benzofuran-5-carboxylic acid as anoff-white solid. HRMS (EI) calcd for C₁₂H₈O₃: 200.0473, found 200.0476(M⁺).

[0699] 3-Prop-1-ynyl-1-benzofuran-5-carboxylic acid (178 mg, 1.0 mmol)is coupled with (R)-3-aminoquinuclidine dihydrochloride (219 mg, 1.1mmol) according to Method A to afford 200 mg (65%) of Example 23 as anoff-white solid. HRMS (ESI) calcd for C₁₉H₂₀N₂O₂+H: 309.1603, found309.1599 (M+H)⁺.

EXAMPLE 24N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-benzofuran-5-carboxamide.fumarate

[0700]

[0701] A mixture of ethyl and methyl 3-bromo-1-benzofuran-5-carboxylate(778 mg, 3.0 mmol) is combined with zinc cyanide (211 mg, 1.8 mmol),tris(dibenzylideneacetone)dipalladium (110 mg, 0.12 mmol),1,1′-bis(diphenylphosphino)ferrocene (132 mg, 0.24 mmol) and zinc dust(46 mg, 0.72 mmol) in a dry flask under nitrogen. The vessel is purgedwith nitrogen, treated with dimethyl acetamide (6 mL) and heated to 120°C. for 18 h. The mixture is cooled to RT diluted with EtOAc (50 mL),filtered through celite and washed with 2N NH₄OH (2×50 mL). The organicsare further washed with NaCl (50 mL), dried (Na₂SO₄) and concentrated toa brown solid (763 mg). The crude material is chromatographed over 30 gslurry-packed silica gel, eluting with 12% EtOAc/hexane. The appropriatefractions are combined and concentrated to afford 280 mg (45%) of themixed methyl and ethyl esters as a yellow solid (45% ethyl ester/55%methyl ester). The mixture of ethyl and methyl3-cyano-1-benzofuran-5-carboxylate (270 mg, 1.3 mmol) is suspended in pH7 buffer (11 mL), treated with a solution of pig liver esterase (64 mg)in pH 7 buffer (4 mL) and stirred vigorously at RT for 16 h. Acetone (2mL) is added, the mixture is stirred for 24 h and filtered throughcelite. The filtrate is acidified to pH 2 with concentrated HCl. Theresulting solid is stirred for 45 min, filtered and dried in a vacuumoven at 80° C. for 16 h to afford 100 mg (41%) of3-cyano-1-benzofuran-5-carboxylic acid as a white solid. MS forC₁₀H₅NO₃, (EI) m/z: 187 (M)⁺.

[0702] 3-Cyano-1-benzofuran-5-carboxylic acid (94 mg, 0.5 mmol) iscoupled with (R)-3-aminoquinuclidine dihydrochloride (109 mg, 0.55 mmol)according to Method A. The free base (123 mg) is combined with fumaricacid (48 mg, 0.41 mmol) in MeOH (0.7 mL) and the fumarate salt isprecipitated upon addition of EtOAc (7 ml). The solid is collected,rinsed with Et₂O, and dried in a vacuum oven at 60° C. to afford 126 mg(61%) of Example 24 as a white solid. HRMS (FAB) calcd for C₁₇H₁₇N₃O₂+H:296.1399, found 296.1403 (M+H)⁺.

EXAMPLE 25N-5-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-3,5-dicarboxamide

[0703]

[0704]N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-benzofuran-5-carboxamide(148 mg, 0.5 mmol) is dissolved in conc. H₂SO₄ (0.5 mL, 18 mmol) andwater (50 μL) and stirred at RT for 4.5 h. The pH is adjusted to 12 with10N NaOH and the resulting solid filtered and rinsed with acetone. Thefiltrate is extracted with 10% MeOH/CHCl₃ (6×20 mL) and the organics aredried (Na₂SO₄) and concentrated to a white foam (173 mg). The foam istriturated with Et₂O, the resulting solid filtered, and dried in avacuum oven at 50° C. to afford 99 mg (63%) of Example 25 as anoff-white solid. HRMS (ESI) calcd for C₁₇H₁₉N₃O₃+H: 314.1505, found314.1502 (M+H)⁺.

EXAMPLE 26N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-5-carboxamidehydrochloride

[0705]

[0706] 1-Benzofuran-5-carboxylic acid (0.177 g) is coupled with(3R,5R)-[3.2.1]-Amine (0.221 g) using Method A, making non-criticalchanges to afford 0.267 g of Example 26 as an off-white foam: ¹H NMR(400 MHz, DMSO-d₆) δ 10.67, 8.50-8.60, 8.32; 8.18, 7.82, 7.69, 7.08,4.40-4.60, 3.05-3.60, 2.65-2.75, 2.05-2.20, 1.85-2.00.

EXAMPLE 27N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-6-carboxamide.fumarate

[0707]

[0708] 1-Benzofuran-5-carboxylic acid (0.762 g) is coupled with(3R,5R)-[3.2.1]-Amine (0.620 g) using Method A, making non-criticalchanges. The free base is treated with EtOH/fumaric acid, heated,partially evaporated, collected by filtration and dried in vaccuo toafford 0.477 g of Example 27 as an off-white solid: ¹H NMR (400 MHz,DMSO-d₆) δ 8.30-8.40, 8.10-8.15, 8.08, 7.70-7.80, 7.00-7.05, 6.51,4.30-4.45, 3.00-3.45, 2.75-2.95, 1.65-2.00.

EXAMPLE 28N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1H-indole-5-carboxamide

[0709]

[0710] Method B

[0711] To a stirred solution of 1H-indole-5-carboxylic acid (80.6 mg,0.5 mmol) in DMF (10 mL) are added DIEA (265 μL, 1.52 mmol) andexo-[2.2.1]-Amine (228 mg, 0.5 mmol). The mixture is cooled to 0° C. inan ice bath, and HATU (190 mg, 0.5 mmol) is added in one portion. Thereaction mixture is allowed to warm to RT and stirs for 2 days. Thesolvent is removed in vacuo and the residue is partitioned betweensaturated aqueous K₂CO₃ solution and chloroform-methanol (95:5). Theaqueous layer is extracted with chloroform-methanol (95:5) twice. Thecombined organic layers are washed with brine, dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The crude product ispurified by flash chromatography on silica gel. Elution withCHCl₃-MeOH—NH₄OH (90:9:1) gives 90 mg (71%) of Example 28 as a whitesolid: ¹H NMR (400 MHz, CD₃OD) δ 8.13, 7.62, 7.44, 7.33, 6.56,3.84-3.81, 3.37, 3.09-3.04, 2.86-2.75, 2.69, 2.60-2.53, 2.45, 1.81-1.72,1.41-1.34.

EXAMPLE 29N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1H-indole-6-carboxamide.fumarate

[0712]

[0713] Method C

[0714] To a stirred solution of 1H-indole-6-carboxylic acid (81 mg, 0.5mmol) in anhydrous DMF (10 mL) are added DEEA (265 μL, 1.52 mmol) andexo-[2.2.1]-Amine (228 mg, 0.5 mmol). The mixture is cooled to 0° C.,and HATU (190 mg, 0.5 mmol) is added in one portion. The reactionmixture is allowed to warm to RT and stirs overnight. The solvent isremoved in vacuo and the residue is partitioned between saturatedaqueous K₂CO₃ solution and chloroform. The aqueous layer is extractedwith chloroform (2×). The combined organic layers are washed with brine,dried (Na₂SO₄), filtered and concentrated in vacuo. The crude product ispurified by flash chromatography on silica gel. Elution withCHCl₃-MeOH—NH₄OH (89:9:1) gives the free base as a yellow solid (84 mg,66%).

[0715] To a stirred solution of the free base (84 mg, 0.33 mmol) inmethanol (5 mL) is added a warm solution of fumaric acid (38 mg, 0.33mmol) in methanol (5 mL). The mixture is stirred for 10 min at 50° C.The solvent is removed in vacuo and the remaining residue is dilutedwith acetone (5 mL). The mixture is stirred overnight at RT. The solidis collected by filtration, washed with acetone, and dried under highvacuum overnight to give 88 mg (72%) of Example 29 as a white solid: ¹HNMR (400 MHz, CD₃OD) δ 11.38, 8.32-8.31, 7.94, 7.58-7.50, 6.54, 6.48,3.86-3.82, 3.15-3.10, 2.97-2.89, 2.67-2.55, 1.78-1.69, 1.38-1.31.

EXAMPLE 30N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-6-carboxamide.fumarate

[0716]

[0717] 1-Benzofuran-6-carboxylic acid is coupled with exo-[2.2.1]-Amineaccording to Method C making non-critical changes to give the free baseas a yellow solid (237 mg, 91%) and Example 30 as a white solid (307 mg,89%): ¹H NMR (400 MHz, CD₃OD) δ 8.07, 7.95-7.94, 7.81-7.72, 6.96-6.95,6.71, 4.27-4.25, 3.75-3.69, 3.47-3.36, 3.27-3.22, 3.08-3.07, 2.23-2.14,1.89-1.81.

EXAMPLE 31N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzothiophene-6-carboxamide.fumarate

[0718]

[0719] 1-Benzothiophene-6-carboxylic acid is coupled withexo-[2.2.1]-Amine according to Method C, allowing the reaction to stirfor 3 days and making non-critical changes to give the free base as awhite solid (272 mg, 100%). The salt is obtained according to Method C,stirring the reaction at 40° C. for 10 min to afford Example 31 as awhite solid (333 mg, 86%): ¹H NMR (400 MHz, CD₃OD) δ 8.47, 7.96, 7.86,7.81, 7.48, 6.71, 4.27-4.24, 3.74-3.68, 3.46-3.35, 3.26-3.20, 3.07,2.22-2.13, 1.87-1.81.

EXAMPLE 32N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-bromo-1-benzofuran-6-carboxamide.fumarate

[0720]

[0721] 3-Bromo-1-benzofuran-6-carboxylic acid is coupled withexo-[2.2.1]-Amine according to Method C, allowing the reaction to stirfor 2 days and making non-critical changes to give the free base as alight yellow oil (287 mg, 100%). The salt is obtained according toMethod C, stirring the reaction at 40° C. for 10 min to afford Example32 as a white solid (303 mg, 80%): ¹H NMR (400 MHz, CD₃OD) δ 8.15, 8.06,7.96, 7.67, 6.71, 4.28-4.26, 3.75-3.70, 3.49-3.37, 3.28-3.23, 3.08,2.23-2.15, 1.89-1.82.

EXAMPLE 33N-[(exo-4R)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-5-carboxamide.fumarate

[0722]

[0723] 1-Benzofuran-5-carboxylic acid is coupled withexo-(4R)-[2.2.1]-Amine according to Method C, allowing the reaction tostir for 2 days and making non-critical changes to give the free base asa yellow solid (510 mg, 100%). The salt is obtained according to MethodC, stirring the reaction at 40° C. for 30 min to afford Example 33 as awhite solid (670 mg, 90%): ¹H NMR (400 MHz, CD₃OD) δ 8.19, 7.89-7.75,7.61, 6.97, 6.71, 4.26-4.23, 3.73-3.68, 3.45-3.35, 3.26-3.20, 3.07,2.21-2.13, 1.88-1.80.

EXAMPLE 34N-[(endo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-5-carboxamide.fumarateandN-[(endo-4R)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-5-carboxamide.fumarate

[0724]

[0725] 1-Benzofuran-5-carboxylic acid is coupled with racemicendo-[2.2.1]-Amine according to Method C, stirring for 2 days, makingnon-critical changes to afford the free base as a recemic mixture (440mg, 98%). The racemic product is resolved by chiral chromatography usinga Chiralcel OJ column to afford 190 mg (43%) of the (−)-enantiomer and160 mg (36%) of the (+)-enantiomer. The fumarate salts of bothenantimers are made according to Method C, making non-critical changes.¹H NMR (400 MHz, CD₃OD) δ 8.21, 7.89-7.85, 7.62, 6.98, 6.71, 4.70-4.65,3.88-3.82, 3.51-3.35, 3.29-3.27, 3.16-3.11, 2.23-2.16, 2.14-2.05.

EXAMPLE 35N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamidehydrochloride

[0726]

[0727] 1-Benzofuran-6-carboxylic acid (0.16 g, 1.0 mmol), HATU (0.46 g,1.2 mmol) and 2S-methyl-2.2.2-Amine (0.213 g, 1.0 mmol) are dissolved in12 mL CH₃CN. DIEA (1.4 mL, 8.0 mmol) is added dropwise. After 3 days,the solvent is removed in vacuo. The residue is taken up in CHCl₃, 1NNaOH is added and the mixture is extracted with CHCl₃. The combinedorganic layers are dried (MgSO₄), filtered and concentrated. The residueis purified by chromatography (Biotage 40S, 90:9:1 CHCl₃/MeOH/NH₄OH).The hydrochloride salt is prepared and recrystallized from MeOH/EtOAc toprovide 203 mg (63%) of the product. HRMS (FAB) calculated forC₁₇H₂₀N₂O₂+H=285.1603, found 285.1617.

EXAMPLE 36N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-5-carboxamidehydrochloride

[0728]

[0729] 1-Benzothiophene-5-carboxylic acid is coupled with2S-methyl-2.2.2-Amine and the hydrochloride salt is prepared followingthe procedure of Example 35, making non-critical changes to affordExample 36 (137 mg, 73%). HRMS (FAB) calculated for C₁₇H₂₀N₂OS+H301.1375, found 301.1380.

EXAMPLE 37N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-5-carboxamide.0.5fumarate

[0730]

[0731] 1-benzofuran-5-carboxylic acid is coupled with 3(R)-[3.2.2]-Amineaccording to Method C making non-critical changes to give the free baseas a white solid (220 mg, 77%) and Example 37 as a white solid (90 mg,66%): ¹H NMR (400 MHz, CD₃OD) δ 8.16, 7.88, 7.82, 7.60, 6.97, 6.69,4.75-4.65, 3.70, 3.50-3.41, 3.41-3.20, 3.04, 2.48-2.33, 2.14-1.93, 1.87.

Materials and Methods for Determining α7 nAChR Agonist Activity

[0732] Cell-Based Assay for Measuring the EC₅₀ of α7 nAChR Agonists

[0733] Construction and Expression of the α7-5HT₃ Receptor:

[0734] The cDNA encoding the N-terminal 201 amino acids from the humanα7 nAChR that contain the ligand binding domain of the ion channel wasfused to the cDNA encoding the pore forming region of the mouse 5HT₃receptor as described by Eisele J L, et al., Chimaericnicotinic-serotonergic receptor combines distinct ligand binding andchannel specificities, Nature (1993), December 2;366(6454):479-83, andmodified by Groppi, et al., WO 00/73431. The chimeric α7-5HT₃ ionchannel was inserted into pGS 175 and pGS 179 which contain theresistance genes for G-418 and hygromycin B, respectively. Both plasmidswere simultaneously transfected into SH-EP1 cells and cell lines wereselected that were resistant to both G-418 and hyrgromycin B. Cell linesexpressing the chimeric ion channel were identified by their ability tobind fluorescent α-bungarotoxin on their cell surface. The cells withthe highest amount of fluorescent α-bungarotoxin binding were isolatedusing a Fluorescent Activated Cell Sorter (FACS). Cell lines that stablyexpressed the chimeric α7-5HT₃ were identified by measuring fluorescentα-bungarotoxin binding after growing the cells in minimal essentialmedium containing nonessential amino acids supplemented with 10% fetalbovine serum, L-glutamine, 100 units/ml penicillin/streptomycin, 250ng/mg fungizone, 400 μg/ml hygromycin B, and 400 μg/ml G-418 at 37° C.with 6% CO₂ in a standard mammalian cell incubator for at least 4 weeksin continuous culture.

[0735] Assay of the Activity of the Chimeric α7-5HT₃ Receptor

[0736] To assay the activity of the α7-5HT₃ ion channel, cellsexpressing the channel were plated into each well of either a 96 or 384well dish (Corning #3614) and grown to confluence prior to assay. On theday of the assay, the cells were loaded with a 1:1 mixture of 2 mMCalcium Green 1, AM (Molecular Probes) dissolved in anhydrous DMSO and20% pluronic F-127 (Molecular Probes). This solution was added directlyto the growth media of each well to achieve a final concentration 2 μM.The cells were incubated with the dye for 60 min at 37° C. and thenwashed with a modified version of Earle's balanced salt solution(MMEBSS) as described in WO 00/73431. The ion conditions of the MMEBSSwas adjusted to maximize the flux of calcium ion through the chimericα7-5HT₃ ion channel as described in WO 00/73431. The activity ofcompounds on the chimeric α7-5HT₃ ion channel was analyzed on FLIPR. Theinstrument was set up with an excitation wavelength of 488 nanometersusing 500 milliwatts of power. Fluorescent emission was measured above525 nanometers with an appropriate F-stop to maintain a maximal signalto noise ratio. Agonist activity of each compound was measured bydirectly adding the compound to cells expressing the chimeric α7-5HT₃ion channel and measuring the resulting increase in intracellularcalcium that is caused by the agonist-induced activation of the chimericion channel. The assay is quantitative such that concentration-dependentincrease in intracelluar calcium is measured as concentration-dependentchange in Calcium Green fluorescence. The effective concentration neededfor a compound to cause a 50% maximal increase in intracellular calciumis termed the EC₅₀. The examples were tested and have EC₅₀ values fromabout 25 nM to about 10,000 nM:

[0737] Binding Constants:

[0738] Another way for measuring α7 nAChR agonist activity is todetermine binding constants of a potential agonist in a competitionbinding assay. For α7 nAChR agonists, there is good correlation betweenfunctional EC₅₀ values using the chimeric α7-5HT₃ ion channel as a drugtarget and binding affinity of compounds to the endogenous α7 nAChR.

[0739] Membrane Preparation.

[0740] Male Sprague-Dawley rats (300-350 g) are sacrificed bydecapitation and the brains (whole brain minus cerebellum) are dissectedquickly, weighed and homogenized in 9 volumes/g wet weight of ice-cold0.32 M sucrose using a rotating pestle on setting 50 (10 up and downstrokes). The homogenate is centrifuged at 1,000×g for 10 minutes at 4°C. The supernatant is collected and centrifuged at 20,000×g for 20minutes at 4° C. The resulting pellet is resuspended to a proteinconcentration of 1-8 mg/mL. Aliquots of 5 mL homogenate are frozen at−80° C. until needed for the assay. On the day of the assay, aliquotsare thawed at rt and diluted with Kreb's—20 mM Hepes buffer pH 7.0 (atrt) containing 4.16 mM NaHCO₃, 0.44 mM KH₂PO₄, 127 mM NaCl, 5.36 mM KCl,1.26 mM CaCl₂, and 0.98 mM MgCl₂, so that 25-150 ,g protein are addedper test tube. Proteins are determined by the Bradford method (Bradford,M. M., Anal. Biochem., 72, 248-254, 1976) using bovine serum albumin asthe standard.

[0741] Binding Assay.

[0742] For saturation studies, 0.4 mL homogenate are added to test tubescontaining buffer and various concentrations of radioligand, and areincubated in a final volume of 0.5 mL for 1 hour at 25° C. Nonspecificbinding was determined in tissues incubated in parallel in the presenceof 0.05 mls MLA for a final concentration of 1 μM, added before theradioligand. In competition studies, drugs are added in increasingconcentrations to the test tubes before addition of 0.05 mls [³H]-MLAfor a final concentration 3.0 to 4.0 nM. The incubations are terminatedby rapid vacuum filtration through Whatman GF/B glass filter papermounted on a 48 well Brandel cell harvester. Filters are pre-soaked in50 mM Tris HCl pH 7.0-0.05% polyethylenimine. The filters are rapidlywashed two times with 5 mL aliquots of cold 0.9% saline and then countedfor radioactivity by liquid scintillation spectrometry.

[0743] Data Analysis.

[0744] In competition binding studies, the inhibition constant (Ki) wascalculated from the concentration dependent inhibition of [³ H]-MLAbinding obtained from non-linear regression fitting program according tothe Cheng-Prusoff equation (Cheng, Y. C. and Prussoff, W. H., Biochem.Pharmacol., 22, p. 3099-3108, 1973). Hill coefficients were obtainedusing non-linear regression (GraphPad Prism sigmoidal dose-response withvariable slope).

1. A method for treating a disease or condition in a mammal in needthereof, wherein the mammal would receive symptomatic relief from theadministration of an α7 nicotinic acetylcholine receptor agonistcomprising administering to the mammal a therapeutically effectiveamount of a compound according to Formula I:

wherein Azabicyclo is

R₁ is H, alkyl, halogenated alkyl, cycloalkyl, substituted phenyl, orsubstituted naphthyl; R₂ is H, F, Cl, Br, I, alkyl, halogenated alkyl,substituted alkyl, cycloalkyl, or aryl; k is 1 or 2, provided that whenk is 2, each R₂ is other than H; R₃ is H, lower alkyl, lower substitutedalkyl, or lower halogenated alkyl; W¹ is O, S, or N(R₁₅); W⁵ and W⁶ areindependently H or a bond to the carbonyl of Formula I, provided thatonly one of W⁵ and W⁶ is said bond and the other is H; Each R₄ isindependently H, F, Cl, Br, I, alkyl, halogenated alkyl, substitutedalkyl, alkenyl, halogenated alkenyl, substituted alkenyl, alkynyl,halogenated alkynyl, substituted alkynyl, cycloalkyl, halogenatedcycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenatedheterocyloalkyl, substituted heterocycloalkyl, lactam heterocylcoalkyl,phenyl, substituted phenyl, —OR₁₀, —SR₁₀, —SOR₁₀, —SO₂R₁₀, —NR₁₀C(O)R₅,—NR₁₀C(O)R₆, —NR₁₀C(O)R₈, —N(R₁₀)₂, —NO₂, —C(O)R₁₀, —CN, —C(O)₂R₁₀,—C(O)NHR₁₀, —SCN, —S(O)NHR₁₀, —S(O)₂NHR₁₀, —NR₁₀S(O)₂R₁₀, R₅, or R₆,provided that when R₄ is —SO₁₋₂R₁₀ or —CO₁₂R₁₀ and R₁₀ is heterocycle,halogenated heterocycle or heterocycle substituted with 1 substitutentselected from R₁₃, a carbon in the heterocycle is bonded to the carbonor sulfur; m is 1 or 2, provided that when m is 2 each R₄ is other thanH; R₅ is a 5-membered heteroaromatic mono-cyclic moiety containingwithin the ring 1-3 heteroatoms independently selected from the groupconsisting of —O—, ═N—, —N(R₁₆)—, and —S—, and having 0-1 substituentselected from R₁, and further having 0-3 substituents independentlyselected from F, Cl, Br, or I, or R₅ is a 9-membered fused-ring moietyhaving a 6-membered ring fused to a 5-membered ring and having theformula

wherein each A is independently CR₁₄ or N, provided that only up to oneA is N, E¹ and E² are independently selected from CR₁₄, O, S, or NR₁₆,and G is CR₁₄, provided that R₁₄ or R₁₆ can be a bond when — forms adouble bond and further provided that only one R₁₄ or R₁₆ can be a bondfor bonding R₅ to a moiety to which it is attached; R₆ is a 6-memberedheteroaromatic mono-cyclic moiety containing within the ring 1-3heteroatoms selected from ═N— and having 0-1 substituent selected fromR₉ and 0-3 substituent(s) independently selected from F, Cl, Br, or I,or R₆ is a 10-membered heteroaromatic bi-cyclic moiety containing withinone or both rings 1-3 heteroatoms selected from ═N—, each 10-memberedfused-ring moiety having 0-1 substituent selected from R₉, and 0-3substituent(s) independently selected from F, Cl, Br, or I; R₇ is H,alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenatedcycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 0-4substituents independently selected from F, Cl, Br, I, and R₉: Each R₈is independently H, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, phenyl, or phenyl substituted with 0-4 independentlyselected from F, Cl, Br, I, or R₉; R₉ is alkyl, substituted alkyl,halogenated alky, —OR₁₁, —CN, —NO₂, —NR₁₀R₁₀; Each R₁₀ is independentlyH, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1substituent selected from R₁₃, cycloalkyl substituted with I substituentselected from R₁₃, heterocycloalkyl substituted with 1 substituentselected from R₁₃, halogenated alkyl, halogenated cycloalkyl,halogenated heterocycloalkyl, phenyl, or substituted phenyl; Each R₁₁ isindependently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, or halogenated heterocycloalkyl; R₁₂ is —OR₁₁,—SR₁₁, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl,substituted cycloalkyl, substituted heterocycloalkyl, —N(R₁₁)₂, R₁₁,—NO₂, —CN(R₁₁)₂, —CN, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂, or —NR₁₁S(O)₂R₁₁; R₁₃is —OR₁₁, —SR₁₁, —N(R₁₁)₂, —C(O)R₁₁, —SOR₁₁, —SO₂R₁₁, —C(O)NR₁₁R₁₁, —CN,—CF₃, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂, —NR₁₁S(O)₂R₁₁, or —NO₂; Each R₁₄ isindependently bond, H, alkyl, cycloalkyl, heterocycloalkyl, halogenatedalkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, substitutedalkyl, substituted cycloalkyl, substituted heterocycloalkyl, —OR₁₁,—SR₁₁, —N(R₁₁)₂, —C(O)R₁₁, —NO₂, —C(O)N(R₁₁)₂, —CN, —NR₁₁C(O)R₁₁,—S(O)₂N(R₁₁)₂, —NR₁₁S(O)₂R₁₁, F, Cl, Br, I, or a bond, provided that thefused-ring moiety has 0-1 substituent selected from alkyl, cycloalkyl,heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenatedheterocycloalkyl, substituted alkyl, substituted cycloalkyl, substitutedheterocycloalkyl, —OR₁₁, —SR₁₁, —N(R₁₁)₂, —C(O)R₁₁, —NO₂, —C(O)N(R₁₁)₂,—CN, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂, or —NR₁₁S(O)₂R₁₁, and further providedthat the fused-ring moiety has 0-3 substituent(s) selected from F, Cl,Br, or I; R₁₅ is H, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, or substitutedheterocycloalkyl; Each R₁₆ is independently bond, H, alkyl, halogenatedalkyl, substituted alkyl, cycloalkyl, halogenated cycloalkyl,substituted cycloalkyl, heterocycloalkyl, halogenated heterocycloalkyl,or substituted heterocycloalkyl; Aryl is phenyl, substituted phenyl,naphthyl, or substituted naphthyl; Substituted phenyl is a phenyl eitherhaving 1-4 substituents independently selected from F, Cl, Br, or I, orhaving 1 substituent selected from R₁₂ and 0-3 substituentsindependently selected from F, Cl, Br, or I; Substituted naphthyl is anaphthalene moiety either having 1-4 substituents independently selectedfrom F, Cl, Br, or I, or having 1 substituent selected from R₁₂ and 0-3substituents independently selected from F, Cl, Br, or I, where thesubstitution can be independently on either only one ring or both ringsof said naphthalene moiety; Alkyl is both straight- and branched-chainmoieties having from 1-6 carbon atoms; Lower alkyl is both straight- andbranched-chain moieties having from 1-4 carbon atoms; Halogenated alkylis an alkyl moiety having from 1-6 carbon atoms and having 1 to (2n+1)substituent(s) independently selected from F, Cl, Br, or I where n isthe maximum number of carbon atoms in the moiety; Lower halogenatedalkyl is an alkyl moiety having from 1-4 carbon atoms and having 1 to(2n+1) substituent(s) independently selected from F, Cl, Br, or I wheren is the maximum number of carbon atoms in the moiety; Substituted alkylis an alkyl moiety from 1-6 carbon atoms and having 0-3 substituentsindependently selected from R₅, R₆, F, Cl, Br, or I and further having 1substituent selected from —OR₁₀, —SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀,—C(O)NR₁₀R₁₀, —CN, —NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀, —NO₂,phenyl, or phenyl having 1 substituent selected from R₉ and furtherhaving 0-3 substituents independently selected from F, Cl, Br, or I:Lower substituted alkyl is lower alkyl having 0-3 substituentsindependently selected from F, Cl, Br, or I, and further having 1substituent selected from —OR₁₀, —SR₁₀, —NR₁₀)₂, —C(O)R₁₀, —C(O)N(R₁₀₎₂, —CN, —NR₁₀C(OR₁₀, —S(O)₂N(R₁₀)₂, —NR₁₀S(O)₂R₁₀, —NO₂, phenyl, R₅, orR₆, wherein each R₁₀ is independently H, lower alkyl, cycloalkyl,heterocycloalkyl, or phenyl. wherein any lower alkyl, cycloalkyl,heterocycloalkyl, or phenyl is optionally substituted with up to twohalogens independently selected from F or Cl and up to one othersubstituent independently selected from —OR₁₁, —SR₁₁, —N(R₁₁)₂,—C(O)R₁₁, —C(O)N(R₁₁)₂, —CN, —CF, NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂,—NR₁₁S(O)₂R₁₁ or —NO₂, and wherein each R₁₁ is independently H, loweralkyl, lower cycloalkyl, heterocycloalkyl, lower halogenated alkyl,lower halogenated cycloalkyl, or halogenated heterocycloalkyl: Alkenylis straight- and branched-chain moieties having from 2-6 carbon atomsand having at least one carbon-carbon double bond: Lower alkenyl isstraight- and branched-chain moieties having from 2-4 carbon atoms andhaving at least one carbon-carbon double bond: Halogenated alkenyl is anunsaturated alkenyl moiety having from 2-6 carbon atoms and having 1 to(2n−1) substituent(s) independently selected from F, Cl, Br, or I wheren is the maximum number of carbon atoms in the moiety: Lower halogenatedalkenyl is an unsaturated alkenyl moiety having from 2-4 carbon atomsand having 1 to (2n−1) substituent(s) independently selected from F, Cl,Br, or I where n is the maximum number of carbon atoms in the moiety:Substituted alkenyl is an unsaturated alkenyl moiety having from 2-6carbon atoms and having 0-3 substituents independently selected from F,or Cl, and further having 1 substituent selected from R₅, R₆, —OR₁₀,—SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —C(O)NR₁₀R₁₀, —NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀,—NR₁₀S(O)₂R₁₀, —CN, phenyl, or phenyl having 1 substituent selected fromR₉, and further having 0-3 substituents independently selected from F,Cl, Br, or I: Lower substituted alkenyl is lower alkenyl having 0-3substituents independently selected from F, Cl, Br, or I, and furtherhaving 1 substituent selected from R₅, R₆, —CN, —OR₁₀, —SR₁₀, —N(R₁₀),—C(O)R₁₀, —C(O)N(R₁₀)₂, —NR₁₀C(O)R₁₀, —S(O)₂N(R₁₀)₂, —NR₁₀S(O)₂R₁₀,—NO₂, phenyl, R₅, or R₆, wherein each R₁₀ is independently H, loweralkyl, cycloalkyl, heterocycloalkyl, or phenyl. wherein any lower alkyl,cycloalkyl, heterocycloalkyl, or phenyl is optionally substituted withup to two halogens independently selected from F or Cl and up to oneother substituent independently selected from —OR₁₁, —SR₁₁, —N(R₁₁)₂,—C(O)R₁₁, —C(O)N(R₁₁)₂, —CN, —CF₃, —NR₁₁OR₁₁, —S(O)₂N(R₁₁)₂,—NR₁₁S(O)₂R₁₁, or —NO₂, and wherein each R₁₁ is independently H, loweralkyl, lower cycloalkyl, heterocycloalkyl, lower halogenated alkyl,lower halogenated cycloalkyl, or halogenated heterocycloalkyl: Alkynylis straight- and branched-chained moieties having from 2-6 carbon atomsand having at least one carbon-carbon triple bond: Lower alkynyl isstraight- and branched-chained moieties having from 2-6 carbon atoms andhaving at least one carbon-carbon triple bond: Halogenated alkynyl is anunsaturated alkynyl moiety having from 3-6 carbon atoms and having 1 to(2n−3) substituent(s) independently selected from F, Cl, Br, or I wheren is the maximum number of carbon atoms in the moiety: Lower halogenatedalkynyl is an unsaturated alkynyl moiety having from 3-4 carbon atomsand having 1 to (2n−3) substituent(s) independently selected from F, Cl,Br, or I where n is the maximum number of carbon atoms in the moiety:Substituted alkynyl is an unsaturated alkynyl moiety having from 3-6carbon atoms and having 0-3 substituents independently selected from F,or Cl, and further having 1 substituent selected from R₅, R₆, —OR₁₀,—SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —C(O)NR₁₀R₁₀, —NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀,—NR₁₀S(O)₂R₁₀, —CN, phenyl, or phenyl having 1 substituent selected fromR₉, and further having 0-3 substituents independently selected from F,Cl, Br, or I: Lower substituted alkynyl is lower alkynyl having 0-3substituents independently selected from F, or Cl, and further having 1substituent selected from R₅, R₆, —OR₁₀, —SR₁₀, —N(R₁₀)₂, —C(O)R₁₀,—C(O)N(R₁₀)₂, —CN, —NR₁₀C(O)R₁₀, —S(O)₂N(R₁₀)₂, —NR₁₀S(O)₂R₁₀, —NO₂,phenyl, R₅, or R₆, wherein each R₁₀ is independently H, lower alkyl,cycloalkyl, heterocycloalkyl, or phenyl, wherein any lower alkyl,cycloalkyl, heterocycloalkyl, or phenyl is optionally substituted withup to two halogens independently selected from F or Cl and up to oneother substituent independently selected from —OR₁₁, —SR₁₁, —N(R₁₁)₂,—C(O)R₁₁, —C(O)N(R₁₁)₂, —CN, —CF₃, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂,—NR₁₁S(O)₂R₁₁, or —NO₂, and wherein each R₁₁ is independently H, loweralkyl, lower cycloalkyl, heterocycloalkyl, lower halogenated alkyl,lower halogenated cycloalkyl, or halogenated heterocycloalkyl;Cycloalkyl is a cyclic alkyl moiety having from 3-6 carbon atoms;Halogenated cycloalkyl is a cyclic moiety having from 3-6 carbon atomsand having 1-4 substituents independently selected from F, or Cl;Substituted cycloalkyl is a cyclic moiety having from 3-6 carbon atomsand having 0-3 substituents independently selected from F, or Cl, andfurther having 1 substituent selected from —OR₁₀, —SR₁₀, —NR₁₀R₁₀,—C(O)R₁₀, —CN, —C(O)NR₁₀R₁₀, —NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀,—NO₂, phenyl, or phenyl having 1 substituent selected from R₉, andfurther having 0-3 substituents independently selected from F, Cl, Br,or I; Heterocycloalkyl is a cyclic moiety having 4-7 atoms with 1-2atoms within the ring being —S—, —N(R₇)—, or —O—; Halogenatedheterocycloalkyl is a cyclic moiety having from 4-7 atoms with 1-2 atomswithin the ring being —S—, —N(R₇)—, or —O—, and having 1-4 substituentsindependently selected from F, or Cl; Substituted heterocycloalkyl is acyclic moiety having from 4-7 atoms with 1-2 atoms within the ring being—S—, —N(R₇)—, or —O— and having 0-3 substituents independently selectedfrom —F, or —Cl, and further having 1 substituent selected from R₅, R₆,—OR₁₀, —SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —C(O)NR₁₀R₁₀, —CN, —NR₁₀C(O)R₁₀, —NO₂,—S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀, phenyl, or phenyl having 1 substituentselected from R₉ and further having 0-3 substituents independentlyselected from F, Cl, Br, or I; Lactam heterocycloalkyl is a cyclicmoiety having from 4-7 atoms with one atom being only nitrogen with thebond to the lactam heterocycloalkyl thru said atom being only nitrogenand having a ═O on a carbon adjacent to said nitrogen, and having up to1 additional ring atom being oxygen sulfur, or nitrogen and furtherhaving 0-2 substituents selected from F, Cl, Br, I, or R₁ where valencyallows; or pharmaceutical composition, pharmaceutically acceptable salt,racemic mixture, and pure enantiomer thereof.
 2. The method of claim 1,wherein m is
 1. 3. (Cancel)
 4. (Cancel)
 5. The method of claim 2,wherein R₂ is H, or methyl.
 6. The method of claim 5, wherein W is5-benzofuranyl, 6-benzofuranyl, 5-benzothienyl, or 6-benzothienyl, anyof which is optionally substituted with lower alkyl, lower halogenatedalkyl, lower alkynyl, halogen, cyano, aminocarbonyl, formyl, or acetyl.7. The method of claim 6, wherein Azabicyclo is II.
 8. The method ofclaim 7, wherein the compound isN-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-6-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-5-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-methyl-1-benzofuran-6-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-methyl-1-benzofuran-5-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-cyano-1-benzofuran-6-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-cyano-1-benzofuran-5-carboxamide;N-6-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-2,6-dicarboxamide;N-5-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-2,5-dicarboxamide;2-acetyl-N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-6-carboxamide;2-acetyl-N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-5-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-formyl-1-benzofuran-6-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-2-formyl-1-benzofuran-5-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-methyl-1-benzofuran-6-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-methyl-1-benzofuran-5-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-isopropyl-1-benzofuran-6-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-isopropyl-1-benzofuran-5-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-chloro-1-benzofuran-6-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-chloro-1-benzofuran-5-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-bromo-1-benzofuran-6-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-bromo-1-benzofuran-5-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-ethynyl-1-benzofuran-6-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-ethynyl-1-benzofuran-5-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-prop-1-ynyl-1-benzofuran-6-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-prop-1-ynyl-1-benzofuran-5-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-cyano-1-benzofuran-6-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-3-cyano-1-benzofuran-5-carboxamide;N-6-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-3,6-dicarboxamide;N-5-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzofuran-3,5-dicarboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzothiophene-6-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1-benzothiophene-5-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1H-indole-6-carboxamide;N-[(exo-4S)-1-azabicyclo[2.2.1]hept-3-yl]-1H-indole-5-carboxamide; or apharmaceutically acceptable salt thereof.
 9. The method of claim 6,wherein Azabicyclo is III and k is
 1. 10. The method of claim 9, whereinthe compound isN-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-6-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-5-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1-benzofuran-6-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-methyl-1-benzofuran-5-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-cyano-1-benzofuran-6-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl)]-2-cyano-1-benzofuran-5-carboxamide;N-6-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-2,6-dicarboxamide;N-5-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-2,5-dicarboxamide;2-acetyl-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-6-carboxamide;2-acetyl-N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-5-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-formyl-1-benzofuran-6-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-2-formyl-1-benzofuran-5-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-methyl-1-benzofuran-6-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-methyl-1-benzofuran-5-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-isopropyl-1-benzofuran-6-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-isopropyl-1-benzofuran-5-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-chloro-1-benzofuran-6-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-chloro-1-benzofuran-5-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-bromo-1-benzofuran-6-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-bromo-1-benzofuran-5-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-ethynyl-1-benzofuran-6-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-ethynyl-1-benzofuran-5-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-6-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-5-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-cyano-1-benzofuran-6-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-3-cyano-1-benzofuran-5-carboxamide;N-6-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-3,6-dicarboxamide;N-5-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzofuran-3,5-dicarboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzothiophene-6-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1-benzothiophene-5-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1H-indole-6-carboxamide;N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]-1H-indole-5-carboxamide; or apharmaceutically acceptable salt thereof.
 11. The method of claim 6,wherein Azabicyclo is IV and k is
 1. 12. The method of claim 11, whereinthe compound isN-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-methyl-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-methyl-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-cyano-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-cyano-1-benzofuran-5-carboxamide;N-6-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-2,6-dicarboxamide;N-5-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-2,5-dicarboxamide;2-acetyl-N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-6-carboxamide;2-acetyl-N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-formyl-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-2-formyl-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-methyl-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-methyl-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-isopropyl-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-isopropyl-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-chloro-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-chloro-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-bromo-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-bromo-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-ethynyl-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-ethynyl-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-prop-1-ynyl-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-prop-1-ynyl-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-cyano-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-3-cyano-1-benzofuran-5-carboxamide;N-6-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-3,6-dicarboxamide;N-5-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzofuran-3,5-dicarboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzothiophene-6-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1-benzothiophene-5-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1H-indole-6-carboxamide;N-[(3R)-1-azabicyclo[3.2.2]non-3-yl]-1H-indole-5-carboxamide; or apharmaceutically acceptable salt thereof.
 13. The method of claim 6,wherein Azabicyclo is V or VI and R₃ is H.
 14. The method of claim 13,wherein the compound isN-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-methyl-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-methyl-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-cyano-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-cyano-1-benzofuran-5-carboxamide;N-6-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-2,6-dicarboxamide;N-5-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-2,5-dicarboxamide;2-acetyl-N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-6-carboxamide;2-acetyl-N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-formyl-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-2-formyl-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-methyl-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-methyl-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-isopropyl-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-isopropyl-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-chloro-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-chloro-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-bromo-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-bromo-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-ethynyl-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-ethynyl-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-prop-1-ynyl-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-prop-1-ynyl-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-cyano-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-3-cyano-1-benzofuran-5-carboxamide;N-6-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-3,6-dicarboxamide;N-5-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzofuran-3,5-dicarboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzothiophene-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-5-yl)-1-benzothiophene-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-methyl-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-methyl-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-cyano-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-cyano-1-benzofuran-5-carboxamide;N-6-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-2,6-dicarboxamide;N-5-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-2,5-dicarboxamide;2-acetyl-N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-6-carboxamide;2-acetyl-N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-formyl- I -benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-2-formyl-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-methyl-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-methyl-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-isopropyl-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-isopropyl-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-chloro-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-chloro-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-bromo-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-bromo-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-ethynyl-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-ethynyl-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-prop-1-ynyl-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-prop-1-ynyl-1-benzofuran-5-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-cyano-1-benzofuran-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-3-cyano-1-benzofuran-5-carboxamide;N-6-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-3,6-dicarboxamide;N-5-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzofuran-3,5-dicarboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzothiophene-6-carboxamide;N-(2-azabicyclo[2.2.1]hept-6-yl)-1-benzothiophene-5-carboxamide; orpharmaceutically acceptable salt thereof. 15-22. (Delete)
 23. A methodfor treating a disease or condition in a mammal in need thereof, whereinthe mammal would receive symptomatic relief from the administration ofan α7 nicotinic acetylcholine receptor agonist comprising administeringto the mammal a therapeutically effective amount of a compound accordingto Formula I:

wherein Azabicyclo is

R₁ is H, alkyl, halogenated alkyl, cycloalkyl, substituted phenyl, orsubstituted naphthyl; R₂ is H, alkyl, halogenated alkyl, substitutedalkyl, cycloalkyl, or aryl; W¹ is O, S, or N(R₁₅); W⁵ and W⁶ areindependently H or a bond to the carbonyl of Formula I, provided thatonly one of W⁵ and W⁶ is said bond and the other is H; Each R4 isindependently H, F, Cl, Br, I, alkyl, halogenated alkyl, substitutedalkyl, alkenyl, halogenated alkenyl, substituted alkenyl, alkynyl,halogenated alkynyl, substituted alkynyl, cycloalkyl, halogenatedcycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenatedheterocyloalkyl, substituted heterocycloalkyl, lactam heterocylcoalkyl,phenyl, substituted phenyl, —OR₁₀, —SR₁₀, —SOR₁₀, —SO₂R₁₀, —NR₁₀C(O)R₅,—NR₁₀C(O)R₆, —NR₁₀C(O)R₈, —N(R₁₀)₂, —NO₂, —C(O)R₁₀, —CN, —C(O)₂R₁₀,—C(O)NHR₁₀, —SCN, —S(O)NHR₁₀, —S(O)₂NHR₁₀, —NR₁₀S(O)₂R₁₀, R₅, or R₆,provided that when R4 is —SO₁₋₂R₁₀ or —CO₁₋₂R₁₀ and R₁₀ is heterocycle,halogenated heterocycle or heterocycle substituted with 1 substitutentselected from R₁₃, a carbon in the heterocycle is bonded to the carbonor sulfur; m is 1 or 2, provided that when m is 2 each R₄ is other thanH; R₅ is a 5-membered heteroaromatic mono-cyclic moiety containingwithin the ring 1-3 heteroatoms independently selected from the groupconsisting of —O—, ═N—, —N(R₁₆)—, and —S—, and having 0-1 substituentselected from R₉, and further having 0-3 substituents independentlyselected from F, Cl, Br, or I, or R₅ is a 9-membered fused-ring moietyhaving a 6-membered ring fused to a 5-membered ring and having theformula

wherein each A is independently CR₁₄ or N, provided that only up to oneA is N, E¹ and E² are independently selected from CR₁₄, O, S, or NR₁₆,and G is CR₁₄, provided that R₁₄ or R₁₆ can be a bond when — forms adouble bond and further provided that only one R₁₄ or R₁₆ can be a bondfor bonding R₅ to a moiety to which it is attached; R₆ is a 6-memberedheteroaromatic mono-cyclic moiety containing within the ring 1-3heteroatoms selected from ═N— and having 0-1 substituent selected fromR₉ and 0-3 substituent(s) independently selected from F, Cl, Br, or I,or R₆ is a 10-membered heteroaromatic bi-cyclic moiety containing withinone or both rings 1-3 heteroatoms selected from ═N—, each 10-memberedfused-ring moiety having 0-1 substituent selected from R₉, and 0-3substituent(s) independently selected from F, Cl, Br, or I; R₇ is H,alkyl, halogenated alkyl, substituted alkyl, cycloalkyl, halogenatedcycloalkyl, substituted cycloalkyl, phenyl, or phenyl having 0-4substituents independently selected from F, Cl, Br, I, and R₉; Each R₈is independently H, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, substitutedheterocycloalkyl, phenyl, or phenyl substituted with 0-4 independentlyselected from F, Cl, Br, I, or R₉; R₉ is alkyl, substituted alkyl,halogenated alky, —OR₁₁, —CN, -NO₂, —NR₁₀R₁₀; Each R₁₀ is independentlyH, alkyl, cycloalkyl, heterocycloalkyl, alkyl substituted with 1substituent selected from R₁₃, cycloalkyl substituted with 1 substituentselected from R₁₃, heterocycloalkyl substituted with I substituentselected from R₁₃, halogenated alkyl, halogenated cycloalkyl,halogenated heterocycloalkyl, phenyl, or substituted phenyl; Each R₁₁ isindependently H, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, or halogenated heterocycloalkyl; R₁₂, —OR₁₁,—SR₁₁, alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl,halogenated cycloalkyl, halogenated heterocycloalkyl, substituted alkyl,substituted cycloalkyl, substituted heterocycloalkyl, —N(R₁₁)₂,—C(O)R₁₁, —NO₂, —C(O)N(R₁₁)₂, —CN, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂, or—NR₁₁S(O)₂R₁₁, R₁₃ is —OR₁₁, —SR₁₁, —N(R₁₁)₂, —C(O)R₁₁, —SOR₁₁, —SO₂R₁₁,—C(O)NR₁₁R₁₁, —CN, —CF₃, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂, —NR₁₁S(O)₂R₁₁, or—NO₂; Each R₁₄ is independently bond, H, alkyl, cycloalkyl,heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenatedheterocycloalkyl, substituted alkyl, substituted cycloalkyl, substitutedheterocycloalkyl, —OR₁₁, —SR₁₁, —N(R₁₁)₂, —C(O)R₁₁, —NO₂, —C(O)N(R₁₁)₂,—CN, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂, —NR₁₁S(O)₂R₁₁F, Cl, Br, I, or a bond,provided that the fused-ring moiety has 0-1 substituent selected fromalkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenatedcycloalkyl, halogenated heterocycloalkyl, substituted alkyl, substitutedcycloalkyl, substituted heterocycloalkyl, —OR₁₁, —SR₁₁, —N(R₁₁)₂,—C(O)R₁₁, —NO₂, —C(O)N(R₁₁)₂, —CN, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂, or—NR₁₁S(O)₂R₁₁, and further provided that the fused-ring moiety has 0-3substituent(s) selected from F, Cl, Br, or I; R₁₅ is H, alkyl,halogenated alkyl, substituted alkyl, cycloalkyl, halogenatedcycloalkyl, substituted cycloalkyl, heterocycloalkyl, halogenatedheterocycloalkyl, or substituted heterocycloalkyl; Each R₁₆ isindependently bond, H, alkyl, halogenated alkyl, substituted alkyl,cycloalkyl, halogenated cycloalkyl, substituted cycloalkyl,heterocycloalkyl, halogenated heterocycloalkyl, or substitutedheterocycloalkyl; Aryl is phenyl, substituted phenyl, naphthyl, orsubstituted naphthyl; Substituted phenyl is a phenyl either having 1-4substituents independently selected from F, Cl, Br, or I, or having 1substituent selected from R₁₂ and 0-3 substituents independentlyselected from F, Cl, Br, or I; Substituted naphthyl is a naphthalenemoiety either having 1-4 substituents independently selected from F, Cl,Br, or I, or having 1 substituent selected from R₁₂ and 0-3 substituentsindependently selected from F, Cl, Br, or I, where the substitution canbe independently on either only one ring or both rings of saidnaphthalene moiety; Alkyl is both straight- and branched-chain moietieshaving from 1-6 carbon atoms; Lower alkyl is both straight- andbranched-chain moieties having from 1-4 carbon atoms; Halogenated alkylis an alkyl moiety having from 1-6 carbon atoms and having 1 to (2n+1)substituent(s) independently selected from F, Cl, Br, or I where n isthe maximum number of carbon atoms in the moiety; Lower halogenatedalkyl is an alkyl moiety having from 1-4 carbon atoms and having 1 to(2n+1) substituent(s) independently selected from F, Cl, Br, or I wheren is the maximum number of carbon atoms in the moiety; Substituted alkylis an alkyl moiety from 1-6 carbon atoms and having 0-3 substituentsindependently selected from R₅, R₆, F, Cl, Br, or I and further having 1substituent selected from —OR₁₀, —SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀,—C(O)NR₁₀R₁₀, —CN, —NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀, —NO₂,phenyl, or phenyl having 1 substituent selected from R₉ and furtherhaving 0-3 substituents independently selected from F, Cl, Br, or I;Lower substituted alkyl is lower alkyl having 0-3 substituentsindependently selected from F, Cl, Br, or I, and further having 1substituent selected from —OR₁₀, —SR₁₀, —N(R₁₀)₂, —C(O)R₁₀,—C(O)N(R₁₀)₂, —CN, —NR₁₀C(O)R₁₀, —S(O)₂N(R₁₀)₂, —NR₁₀S(O)₂R₁₀, —NO₂,phenyl, R₅, or R₆, wherein each R₁₀ is independently H, lower alkyl,cycloalkyl, heterocycloalkyl, or phenyl, wherein any lower alkyl,cycloalkyl, heterocycloalkyl, or phenyl is optionally substituted withup to two halogens independently selected from F or Cl and up to oneother substituent independently selected from —OR₁₁, —SR₁₁, —N(R₁₁)₂,—C(O)R₁₁, —C(O)N(R₁₁)₂, —CN, —CF₃, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂,—NR₁₁S(O)₂R₁₁, or —NO₂, and wherein each R₁₁ is independently H, loweralkyl, lower cycloalkyl, heterocycloalkyl, lower halogenated alkyl,lower halogenated cycloalkyl, or halogenated heterocycloalkyl; Alkenylis straight- and branched-chain moieties having from 2-6 carbon atomsand having at least one carbon-carbon double bond; Lower alkenyl isstraight- and branched-chain moieties having from 2-4 carbon atoms andhaving at least one carbon-carbon double bond; Halogenated alkenyl is anunsaturated alkenyl moiety having from 2-6 carbon atoms and having 1 to(2n−1) substituent(s) independently selected from F, Cl, Br, or I wheren is the maximum number of carbon atoms in the moiety; Lower halogenatedalkenyl is an unsaturated alkenyl moiety having from 2-4 carbon atomsand having 1 to (2n−1) substituent(s) independently selected from F, Cl,Br, or I where n is the maximum number of carbon atoms in the moiety;Substituted alkenyl is an unsaturated alkenyl moiety having from 2-6carbon atoms and having 0-3 substituents independently selected from F,or Cl, and further having 1 substituent selected from R₅, R₆, —OR₁₀,—SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —C(O)NR₁₀R₁₀, —NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀,—NR₁₀S(O)₂R₁₀, —CN, phenyl, or phenyl having 1 substituent selected fromR₉, and further having 0-3 substituents independently selected from F,Cl, Br, or I; Lower substituted alkenyl is lower alkenyl having 0-3substituents independently selected from F, Cl, Br, or I, and furtherhaving 1 substituent selected from R₅, R₆, —CN, —OR₁₀, —SR₁₀, —N(R₁₀)₂,—C(O)R₁₀, —C(O)N(R₁₀)₂, —NR₁₀C(O)R₁₀, —S(O)₂N(R₁₀)₂, —NR₁₀S(O)₂R₁₀,—NO₂, phenyl, R₅, or R₆, wherein each R₁₀ is independently H, loweralkyl, cycloalkyl, heterocycloalkyl, or phenyl, wherein any lower alkyl,cycloalkyl, heterocycloalkyl, or phenyl is optionally substituted withup to two halogens independently selected from F or Cl and up to oneother substituent independently selected from —OR₁₁, —SR₁₁, —N(R₁₁)₂,—C(O)R₁₁, —C(O)N(R₁₁)₂, —CN, —CF₃, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂,—NR₁₁S(O)₂R₁₁or —NO₂, and wherein each R₁₁ is independently H, loweralkyl, lower cycloalkyl, heterocycloalkyl, lower halogenated alkyl,lower halogenated cycloalkyl, or halogenated heterocycloalkyl; Alkynylis straight- and branched-chained moieties having from 2-6 carbon atomsand having at least one carbon-carbon triple bond; Lower alkynyl isstraight- and branched-chained moieties having from 2-6 carbon atoms andhaving at least one carbon-carbon triple bond; Halogenated alkynyl is anunsaturated alkynyl moiety having from 3-6 carbon atoms and having 1 to(2n−3) substituent(s) independently selected from F, Cl, Br, or I wheren is the maximum number of carbon atoms in the moiety; Lower halogenatedalkynyl is an unsaturated alkynyl moiety having from 3-4 carbon atomsand having 1 to (2n−3) substituent(s) independently selected from F, Cl,Br, or I where n is the maximum number of carbon atoms in the moiety;Substituted alkynyl is an unsaturated alkynyl moiety having from 3-6carbon atoms and having 0-3 substituents independently selected from F,or Cl, and further having 1 substituent selected from R₅, R₆, —OR₁₀,—SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —C(O)NR₁₀R₁₀, —NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀,—NR₁₀S(O)₂R₁₀, —CN, phenyl, or phenyl having 1 substituent selected fromR₉, and further having 0-3 substituents independently selected from F,Cl, Br, or I; Lower substituted alkynyl is lower alkynyl having 0-3substituents independently selected from F, or Cl, and further having 1substituent selected from R₅, R₆, —OR₁₀, —SR₁₀, —N(R₁₀)₂, —C(O)R₁₀,—C(O)N(R₁₀)₂, —CN, —NR₁₀C(O)R₁₀, —S(O)₂N(R₁₀)₂, —NR₁₀S(O)₂R₁₀, —NO₂,phenyl, R₅, or R₆, wherein each R₁₀ is independently H, lower alkyl,cycloalkyl, heterocycloalkyl, or phenyl, wherein any lower alkyl,cycloalkyl, heterocycloalkyl, or phenyl is optionally substituted withup to two halogens independently selected from F or Cl and up to oneother substituent independently selected from —OR₁₁, —SR₁₁, —N(R₁₁)₂,—C(O)R₁₁, —C(O)N(R₁₁)₂, —CN, —CF₃, —NR₁₁C(O)R₁₁, —S(O)₂N(R₁₁)₂,—NR₁₁S(O)₂R₁₁, or —NO₂, and wherein each R₁₁ is independently H, loweralkyl, lower cycloalkyl, heterocycloalkyl, lower halogenated alkyl,lower halogenated cycloalkyl, or halogenated heterocycloalkyl;Cycloalkyl is a cyclic alkyl moiety having from 3-6 carbon atoms:Halogenated cycloalkyl is a cyclic moiety having from 3-6 carbon atomsand having 1-4 substituents independently selected from F, or Cl;Substituted cycloalkyl is a cyclic moiety having from 3-6 carbon atomsand having 0-3 substituents independently selected from F, or Cl, andfurther having 1 substituent selected from —OR₁₀, —SR₁₀, —NR₁₀R₁₀,—C(O)R₁₀, —CN, —C(O)NR₁₀R₁₀, —NR₁₀C(O)R₁₀, —S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀,—NO₂, phenyl, or phenyl having 1 substituent selected from R₉, andfurther having 0-3 substituents independently selected from F, Cl, Br,or I; Heterocycloalkyl is a cyclic moiety having 4-7 atoms with 1-2atoms within the ring being —S—, —N(R₇)—, or —O—; Halogenatedheterocycloalkyl is a cyclic moiety having from 4-7 atoms with 1-2 atomswithin the ring being —S—, —N(R₇)—, or —O—, and having 1-4 substituentsindependently selected from F, or Cl; Substituted heterocycloalkyl is acyclic moiety having from 4-7 atoms with 1-2 atoms within the ring being—S—, —N(R₇)—, or —O— and having 0-3 substituents independently selectedfrom —F, or —Cl, and further having 1 substituent selected from R₅, R₆,—OR₁₀, —SR₁₀, —NR₁₀R₁₀, —C(O)R₁₀, —C(O)NR₁₀R₁₀, —CN, —NR₁₀C(O)R₁₀, —NO₂,—S(O)₂NR₁₀R₁₀, —NR₁₀S(O)₂R₁₀, phenyl, or phenyl having 1 substituentselected from R₉ and further having 0-3 substituents independentlyselected from F, Cl, Br, or I; Lactam heterocycloalkyl is a cyclicmoiety having from 4-7 atoms with one atom being only nitrogen with thebond to the lactam heterocycloalkyl thru said atom being only nitrogenand having a ═O on a carbon adjacent to said nitrogen, and having up to1 additional ring atom being oxygen, sulfur, or nitrogen and furtherhaving 0-2 substituents selected from F, Cl, Br, I, or R₉ where valencyallows: or pharmaceutical composition, pharmaceutically acceptable salt,racemic mixture, or pure enantiomer thereof.
 24. The method of claim 23,wherein R₁ is H, lower alkyl, or cycloalkyl.
 25. (Delete)
 26. The methodof claim 24, wherein R₂ is H, or methyl.
 27. The method of claim 26,wherein m is 1 and W is 5-benzofuranyl, 6-benzofuranyl, 5-benzothienyl,or 6-benzothienyl, any of which is optionally substituted with loweralkyl, lower halogenated alkyl, lower alkynyl, halogen, cyano,aminocarbonyl, formyl, or acetyl.
 28. (Delete)
 29. The method of claim27, wherein the compound isN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyano-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-cyano-1-benzofuran-5-carboxamide;N-6-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2,6-dicarboxamide;N-5-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2,5-dicarboxamide;2-acetyl-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamide;2-acetyl-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-formyl-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-2-formyl-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-isopropyl-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-isopropyl-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-chloro-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-chloro-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethynyl-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-ethynyl-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-5-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-benzofuran-6-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-benzofuran-5-carboxamide;N-6-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-3,6-dicarboxamide;N-5-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-3,5-dicarboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-6-carboxamide;N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-5-carboxamide; ora pharmaceutically acceptable salt thereof.
 30. The method of claim 27,wherein the compound isN-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-5-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1-benzofuran-6-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-methyl-1-benzofuran-5-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-cyano-1-benzofuran-6-carboxamide;N-[(2S,3R)-2-methyl-(1-azabicyclo[2.2.2]oct-3-yl)]-2-cyano-1-benzofuran-5-carboxamide;N-6-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2,6-dicarboxamide;N-5-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2,5-dicarboxamide;2-acetyl-N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-6-carboxamide;2-acetyl-N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-5-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-formyl-1-benzofuran-6-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-2-formyl-1-benzofuran-5-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-benzofuran-6-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-methyl-1-benzofuran-5-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-isopropyl-1-benzofuran-6-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-isopropyl-1-benzofuran-5-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-chloro-1-benzofuran-6-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-chloro-1-benzofuran-5-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-6-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzofuran-5-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethynyl-1-benzofuran-6-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-ethynyl-1-benzofuran-5-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-6-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-prop-1-ynyl-1-benzofuran-5-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-benzofuran-6-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-3-cyano-1-benzofuran-5-carboxamide;N-6-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-3,6-dicarboxamide;N-5-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-3,5-dicarboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-6-carboxamide;N-[(2S,3R)-2-methyl-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-5-carboxamide;or pharmaceutically acceptable salt thereof. 31-44. (Delete)
 45. Themethod of claim 1, wherein the disease or condition is cognitive andattention deficit symptoms of Alzheimer's, neurodegeneration associatedwith diseases such as Alzheimer's disease, pre-senile dementia (mildcognitive impairment), senile dementia, schizophrenia, psychosis,attention deficit disorder, attention deficit hyperactivity disorder,depression, anxiety, general anxiety disorder, post traumatic stressdisorder, mood and affective disorders, amyotrophic lateral sclerosis,borderline personality disorder, traumatic brain injury, behavioral andcognitive problems in general and associated with brain tumors, AIDSdementia complex, dementia associated with Down's syndrome, dementiaassociated with Lewy Bodies, Huntington's disease, Parkinson's disease,tardive dyskinesia, Pick's disease, dysregulation of food intakeincluding bulemia and anorexia nervosa, withdrawal symptoms associatedwith smoking cessation and dependant drug cessation, Gilles de laTourette's Syndrome, age-related macular degeneration, glaucoma,neurodegeneration associated with glaucoma, or symptoms associated withpain.
 46. The method of claim 1, wherein the disease or condition isattention deficit disorder, or attention deficit hyperactivity disorder.47. The method of claim 1, wherein the disease or condition isdepression, general anxiety disorder, or post traumatic stress disorder.48. The method of claim 1, wherein the disease or condition is cognitiveand attention deficit symptoms of Alzheimer's, neurodegenerationassociated with diseases such as Alzheimer's disease, pre-seniledementia, or senile dementia.
 49. The method of claim 1, wherein thedisease or condition is schizophrenia or psychosis.
 50. The method ofclaim 8, wherein the disease or condition is cognitive and attentiondeficit symptoms of Alzheimer's, neurodegeneration associated withdiseases such as Alzheimer's disease, pre-senile dementia (mildcognitive impairment), senile dementia, schizophrenia, psychosis,attention deficit disorder, attention deficit hyperactivity disorder,depression, anxiety, general anxiety disorder, post traumatic stressdisorder, mood and affective disorders, traumatic brain injury,behavioral and cognitive problems in general and associated with braintumors, AIDS dementia complex, dementia associated with Down's syndrome,dementia associated with Lewy Bodies, Huntington's disease, Parkinson'sdisease, or symptoms associated with pain.
 51. The method of claim 10,wherein the disease or condition is cognitive and attention deficitsymptoms of Alzheimer's, neurodegeneration associated with diseases suchas Alzheimer's disease, pre-senile dementia (mild cognitive impairment),senile dementia, schizophrenia, psychosis, attention deficit disorder,attention deficit hyperactivity disorder, depression, anxiety, generalanxiety disorder, post traumatic stress disorder, mood and affectivedisorders, traumatic brain injury, behavioral and cognitive problems ingeneral and associated with brain tumors, AIDS dementia complex,dementia associated with Down's syndrome, dementia associated with LewyBodies, Huntington's disease, Parkinson's disease, or symptomsassociated with pain.
 52. The method of claim 12, wherein the disease orcondition is cognitive and attention deficit symptoms of Alzheimer's,neurodegeneration associated with diseases such as Alzheimer's disease,pre-senile dementia (mild cognitive impairment), senile dementia,schizophrenia, psychosis, attention deficit disorder, attention deficithyperactivity disorder, depression, anxiety, general anxiety disorder,post traumatic stress disorder, mood and affective disorders, traumaticbrain injury, behavioral and cognitive problems in general andassociated with brain tumors, AIDS dementia complex, dementia associatedwith Down's syndrome, dementia associated with Lewy Bodies, Huntington'sdisease, Parkinson's disease, or symptoms associated with pain.
 53. Themethod of claim 23, wherein the disease or condition is cognitive andattention deficit symptoms of Alzheimer's, neurodegeneration associatedwith diseases such as Alzheimer's disease, pre-senile dementia (mildcognitive impairment), senile dementia, schizophrenia, psychosis,attention deficit disorder, attention deficit hyperactivity disorder,depression, anxiety, general anxiety disorder, post traumatic stressdisorder, mood and affective disorders, amyotrophic lateral sclerosis,borderline personality disorder, traumatic brain injury, behavioral andcognitive problems in general and associated with brain tumors, AIDSdementia complex, dementia associated with Down's syndrome, dementiaassociated with Lewy Bodies, Huntington's disease, Parkinson's disease,tardive dyskinesia, Pick's disease, dysregulation of food intakeincluding bulemia and anorexia nervosa, withdrawal symptoms associatedwith smoking cessation and dependant drug cessation, Gilles de laTourette's Syndrome, age-related macular degeneration, glaucoma,neurodegeneration associated with glaucoma, or symptoms associated withpain.
 54. The method of claim 23, wherein the disease or condition isattention deficit disorder, attention deficit hyperactivity disorder,depression, general anxiety disorder, post traumatic stress disorder,cognitive and attention deficit symptoms of Alzheimer's,neurodegeneration associated with diseases such as Alzheimer's disease,pre-senile dementia, senile dementia, schizophrenia, psychosis, orsymptoms associated with pain.
 55. The method of claim 23, wherein thedisease or condition is attention deficit disorder, or attention deficithyperactivity disorder.
 56. The method of claim 23, wherein the diseaseor condition is depression, general anxiety disorder, or post traumaticstress disorder.
 57. The method of claim 23, wherein the disease orcondition is cognitive and attention deficit symptoms of Alzheimer's,neurodegeneration associated with diseases such as Alzheimer's disease,pre-senile dementia, or senile dementia.
 58. The method of claim 23,wherein the disease or condition is schizophrenia or psychosis.
 59. Themethod of claim 29, wherein the disease or condition is cognitive andattention deficit symptoms of Alzheimer's, neurodegeneration associatedwith diseases such as Alzheimer's disease, pre-senile dementia (mildcognitive impairment), senile dementia, schizophrenia, psychosis,attention deficit disorder, attention deficit hyperactivity disorder,depression, anxiety, general anxiety disorder, post traumatic stressdisorder, mood and affective disorders, traumatic brain injury,behavioral and cognitive problems in general and associated with braintumors, AIDS dementia complex, dementia associated with Down's syndrome,dementia associated with Lewy Bodies, Huntington's disease, Parkinson'sdisease, or symptoms associated with pain.
 60. The method of claim 29,wherein the disease or condition is attention deficit disorder,attention deficit hyperactivity disorder, depression, general anxietydisorder, post traumatic stress disorder, cognitive and attentiondeficit symptoms of Alzheimer's, neurodegeneration associated withdiseases such as Alzheimer's disease, pre-senile dementia, seniledementia, schizophrenia, psychosis, or symptoms associated with pain.